| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe Ulcerative colitis or moderate to severe Crohn's disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ulcerative colitis or Crohn's disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011400 |
| E.1.2 | Term | Crohn's colitis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to characterize the efficacy of TEV-48574 sc administered every two weeks (Q2W) in adult patients with Inflammatory Bowel disease (IBD) (moderate to severe UC or CD), as assessed by induction of clinical remission (UC) and endoscopic response (CD) at week 14. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of 2 different doses of TEV-48574 sc administered Q2W in adult patients with IBD (moderate to severe UC or CD) as assessed by multiple standard measures at week 14.
Other:
- to evaluate the safety and tolerability of 2 doses of TEV-48574
- to evaluate the immunogenicity of 2 doses
Exploratory objectives include:
- to evaluate the efficacy of 2 different doses
- to evaluate the safety and tolerability of 2 different doses
- evaluate association among exploratory biomarkers and clinical efficacy of TEV 48574
- to obtain trough serum TEV 48574 concentrations, to compare major pharmacokinetic characteristics between UC and CD patients with healthy volunteers and asthma patients, and, if data allows, to evaluate the pharmacokinetics/PD or exposure-response relationship of different doses of TEV-48574 sc
- to evaluate the effect of genetic polymorphisms on clinical efficacy in adult patients with IBD (moderate to severe UC or CD) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. Adults of male and female sex (without restrictions on gender) between 18 and 75 years of age, inclusive, at the time of informed consent.
b. Diagnosis of UC or CD for ≥3 months.
c. UC patients only: Patient with moderate to severe active UC as defined by the 3-component modified Mayo score of 5 to 9, inclusive, with an endoscopic subscore of ≥2 (from central reading)
d. CD patients only: Patient with moderate to severe active CD as determined by a CDAI score of ≥220 and ≤450.
e. CD patients only: SES CD score of ≥6 (≥4 for isolated ileal disease).
f. UC patients only: Active disease beyond the rectum (>15 cm of active disease at the screening endoscopy [sigmoidoscopy]).
g. Patient must have inadequate response to, loss of response to, or intolerance to:
- At least 1 of the following therapies: corticosteroids, immunosuppressants, or an approved advanced therapy for IBD including biologics (anti-TNF, anti-integrins, anti-IL-12/23, or anti-IL-23), JAK inhibitors, or S1P receptor modulators. No more than 3 locally approved classes of biologics.
• Inadequate response to, loss of response to, or intolerance to corticosteroid treatment is defined as 1 or more of the following:
- Steroid refractory: persistent symptoms of active disease despite treatment with at least one 4-week induction regimen that included a dose of ≥30 mg prednisone (oral) daily for at least 2 weeks or intravenous (iv) for at least 1 week within the previous 5 years;
- Steroid dependent: 2 failed attempts to taper steroids below a dose equivalent to 10 mg prednisone (oral) daily within the previous year;
- Steroid intolerant: history of intolerance to corticosteroids (including, but not limited to, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection) within the previous 5 years.
• Inadequate response to, loss of response to, or intolerance to prior immunosuppressant treatment is defined by 1 or more of the following:
- Persistent signs and symptoms of active disease despite a history of at least 1 regimen of oral azathioprine (AZA) or 6-mercaptopurine (6-MP) and/or methotrexate consistent with the regional standard of care.
- History of intolerance to AZA, 6-MP, or methotrexate (including, but not limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function testing abnormalities, lymphopenia, thiopurine methyltransferase genetic mutation, and infection).
• Inadequate response to, loss of response to, or intolerance to prior advanced therapy for IBD (biologics, JAK inhibitors, and S1P receptor modulators) defined as 1 or more of the following:
- Loss of response: Persistent signs and symptoms of active disease despite at least one induction and one maintenance regimen of the locally approved regimen of anti-TNF, anti-integrins, anti-IL-12/23 or anti-IL-23 monoclonal antibodies (mAbs), JAK inhibitors, or S1P receptor modulators.
- Inadequate response (primary non-response): Persistent signs and symptoms of active disease despite at least one induction regimen of the locally approved highest dosing regimen of anti-TNF, anti-integrins, anti-IL-12/23 or anti-IL-23 mAbs, JAK inhibitors, or S1P receptor modulators.
- Intolerance: Discontinuation of anti-TNF, anti-integrins, anti-IL-12/23 or anti-IL-23 mAbs, JAK inhibitors, or S1P receptor modulators due to an adverse drug reaction as determined by treating physician. Such adverse drug reactions include, but are not limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function testing abnormalities, lymphopenia, and infections.
h. If patient is taking the following agents, patient must have been on a stable dose for the following specified period of time: oral 5-aminosalicylic acid (5-ASA) or sulfasalazine stable dose for at least 4 weeks prior to endoscopy, oral corticosteroids stable dose for at least 2 weeks prior to endoscopy, and 6-MP, AZA, or methotrexate stable dose for 4 weeks prior to endoscopy.
i. The patient is able to communicate satisfactorily with the investigator and to participate in, and comply with, the requirements of the study.
l. Women of non-childbearing potential who are either surgically (documented hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or congenitally sterile as assessed by a physician, or 1-year postmenopausal. Women of childbearing potential (WOCBP) must have a negative β-human chorionic gonadotropin test result and practice a highly effective method of birth control (methods that can achieve a failure rate of less than 1% per year when used consistently and correctly; Appendix E) prior to IMP administration and throughout the study or 50 days after the last IMP dose, whichever is longer.
m. Male patients (including vasectomized) with WOCBP partners (whether pregnant or not) must use condoms after the first IMP administration and throughout the study or until 50 days after the last IMP dose, whichever is longer. |
|
| E.4 | Principal exclusion criteria |
a. The patient has any concomitant conditions or treatments that could interfere with study conduct, influence the interpretation of study observations/results, or put the patient at increased risk during the study as judged by the investigator and/or the clinical study physician.
b. Diagnosis of indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis.
c. Patient has colonic dysplasia or neoplasia (with exception of dysplasia on a completely excised adenomatous polyp [not a sessile one]), toxic megacolon, primary sclerosing cholangitis, known non-passable colonic stricture, presence of colonic or small bowel stoma, presence of non-passable colonic or small bowel obstruction or resection preventing the endoscopy procedure, or fulminant colitis.
d. Presence of active enteric infections (positive stool culture) or a history of serious infection (requiring parenteral antibiotic and/or hospitalization) within 4 weeks prior to the first screening visit.
e. Patient anticipates requiring major surgery during this study.
f. Hepatitis B core antibody (HBcAb) or surface antigen (HBsAg) positive. If HBcAb is positive and/or HBsAg negative, Hepatitis B viral deoxyribonucleic acid (DNA) will be done as reflective test, and, if undetectable, then not exclusionary. Hepatitis C antibody positive with detectable RNAs. Positive human immunodeficiency virus types 1 or 2 at screening.
g. Tested positive for tuberculosis (TB) at screening by the QuantiFERON® TB Gold Test (unless documentation of prior TB treatment is available) or had a history of untreated latent or active TB.
h. A history of an opportunistic infection (eg, cytomegalovirus retinitis, Pneumocystis carinii, or aspergillosis).
i. A history of more than 2 herpes zoster episodes in the last 5 years or multimetameric herpes zoster.
j. A history of or ongoing chronic or recurrent serious infectious disease (eg, infected indwelling prosthesis or osteomyelitis).
k. Current or history of chronic liver or biliary disease (with the exception of Gilbert’s syndrome, asymptomatic gallstones or uncomplicated fatty liver disease) at screening or baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2x upper limit of normal (ULN) or bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening.
l. Absolute neutrophil count <1.5x10^9/L or Hemoglobin <9 g/dL or lymphocyte count <0.8x10^9/L or platelet count <100,000/mL
m. The patient has QTc>480 ms
n. Any acute infection which in the opinion of the investigator compromises the safety of the patient.
o. The patient is currently pregnant or lactating or is planning to become pregnant or to lactate during the study or for at least 50 days after administration of the last dose of IMP in case of early termination. Any woman becoming pregnant during the study will be withdrawn from the study.
p. The patient has a known hypersensitivity to the IMP and/or excipients.
q. Presence of a transplanted organ.
r. A history of malignancy within the last 5 years (exception: basal cell carcinoma or in situ carcinoma of the cervix if successful curative therapy occurred at least 12 months prior to screening or curatively resected papillary thyroid cancer).
s. Patient is receiving any of the following therapies within the designated time period:
- The patient is currently using any systemic immunosuppressant or immunomodulatory biologic or nonbiologic (other than those listed in inclusion criterion “h” and those that are used for IBD) within 30 days or 5 half-lives (whichever is longer) prior to the endoscopy.
- >9 mg/day of oral budesonide or >20 mg/day prednisone or equivalent within 2 weeks prior to the endoscopy.
- Topical (rectal) treatment of 5-ASA or intravenous, intramuscular (parenteral), or enema/suppository administration of corticosteroids within 2 weeks prior to the endoscopy.
- Biologics including anti-TNF, anti-integrins, anti-IL-12/23, or anti-IL-23 within 3 half-lives prior to randomization.
- Small molecules including JAK inhibitors, or S1P receptor modulators, within 5 half-lives or shorter washout duration if undetectable drug levels can be demonstrated prior to randomization.
- Other investigational procedures or products, within 30 days or 5 half-lives of investigational product prior to the endoscopy, whichever is longer.
- Live vaccine within 14 days prior to the first screening visit. Inactivated vaccines (including approved inactivated coronavirus disease 2019 [COVID-19] vaccines) should preferably be completed 14 days before first IMP dosing. If administered during the study, it is recommended to be at least 3 days before and after IMP administration, or as required by local country regulations.
t. Current or history (within 2 years) of serious psychiatric disease or alcohol or drug abuse. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is response (yes or no) at week 14, where response in UC patients is defined as clinical remission and response in CD patients is defined as endoscopic response. Clinical remission and endoscopic response are determined as follows:
• Clinical remission at week 14 in patients with moderate to severe UC. Clinical remission is a modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score of ≤2 points, which is defined by:
- stool frequency subscore of 0 or 1,
- rectal bleeding subscore of 0, and
- endoscopic subscore of 0 or 1, where a score of 1 does not include “friability”
• Endoscopic response at week 14 in patients with moderate to severe CD, defined as a reduction in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of at least 50% from baseline
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response (yes or no) at week 14, where response in UC patients is defined as clinical remission and response in CD patients is defined as endoscopic response |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints to be measured in patients with moderate to severe UC are as follows:
• Clinical response at week 14, defined as a decrease from baseline in the modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score of at least 2 points AND at least a 30% reduction from baseline with either a decrease in rectal bleeding subscore of at least 1 or an absolute rectal bleeding subscore of less than or equal to 1
• Endoscopic improvement defined as a Mayo endoscopic subscore of 0 or 1 at week 14
• Endoscopic remission defined as a Mayo endoscopic subscore of 0 at week 14
• Clinical response defined as decrease from baseline of at least 50% in 2-item patient-reported outcome (PRO2; rectal bleeding and stool frequency) at week 14
• Clinical remission defined as score of rectal bleeding = 0 and stool frequency = 0 on the PRO2 scale at week 14
The secondary efficacy endpoints to be measured in patients with moderate to severe CD are as follows:
• Clinical response defined as a ≥100-point decrease in Crohn’s Disease Activity Index (CDAI) score from baseline at weeks 4, 8, 12 and 14
• Clinical remission defined as a CDAI score <150 at week 14
• Clinical response defined as a decrease from baseline of at least 50% in PRO2 (PRO2 is defined as having 2 components, abdominal pain and stool frequency) at week 14
• Clinical remission defined as abdominal pain ≤1 and stool frequency ≤3 on the PRO2 scale at week 14
• Endoscopic response defined as a decrease in modified multiplier (MM)-SES-CD of >50% from baseline at week 14
The safety and tolerability measures/parameters are as follows:
• Adverse events
• Change from baseline in clinical laboratory test results (serum chemistry, hematology, and urinalysis)
• Change from baseline in vital signs measurements (blood pressure, pulse rate, body temperature, and respiratory rate)
• Change from baseline in 12-lead electrocardiogram (ECG) findings
• Patients who stopped the IMP due to adverse events
• Local tolerability at the injection site
The immunogenicity endpoints for this study are as follows:
• Change from baseline in treatment-emergent anti-drug antibody (ADA) at weeks 2, 4, 8, 14, and follow-up visit
• Presence of neutralizing ADA in ADA positive patients at weeks 2, 4, 8, 14, and follow-up visit
Exploratory endpoints include:
The exploratory efficacy endpoints to be measured in patients with moderate to severe UC are as follows:
• Clinical response defined as decrease from baseline of at least 50% in 2-item PRO2 (rectal bleeding and stool frequency) at weeks 2, 4, 6, 8, 10, and 12
• Clinical remission defined as score of rectal bleeding = 0 and stool frequency = 0 on the PRO2 scale at weeks 2, 4, 6, 8, 10, and 12
• Histological remission defined as a Robarts Histopathology Index of ≤5 at week 14
• Histological remission defined as Geboes index score ≤3.1 at week 14
The exploratory efficacy endpoints to be measured in patients with moderate to severe CD are as follows:
• Clinical response defined as a decrease from baseline of at least 50% in PRO2 (PRO2 is defined as having 2 components, abdominal pain and stool frequency) at weeks 2, 4, 6, 8, 10, and 12
• Clinical remission defined as abdominal pain ≤1 and stool frequency ≤3 on the PRO2 scale at weeks 2, 4, 6, 8, 10, and 12
• Endoscopic remission defined as SES CD score of 0-2, or SES CD score of 0-4, with no individual sub score >1 at week 14
• Histologic response defined as a ≥50% decrease in Global Histologic Activity Score from baseline at week 14
• Use of concomitant medication
• Device-related adverse events and malfunctions (for the commercial sc infusion system)
• Change from baseline at weeks 2, 4, 8, and 14 in protocol-specified serum-resident pharmacodynamic (PD) markers
• Change from baseline in serum and/or gastrointestinal (GI) tissue markers of GI tissue condition (at weeks 2, 4, 8, and 14 for serum; at week 14 for tissue)
• Change from baseline at week 14 in GI tissue transcriptome
• Change from baseline in fecal calprotectin or other stool-derived markers at weeks 2, 4, 8, and 14
• Change from baseline in high sensitivity C-reactive protein (hsCRP) at weeks 2, 4, 8, and 14
• Change from baseline in serum free and total TL1A at weeks 2, 4, 8, and 14
• Change from baseline at week 14 in GI tissue TL1A expression
• Change from baseline in UC-100 at week 14 in patients with moderate to severe UC
• Change from baseline in protein and/or ribonucleic acid (RNA) expression in peripheral blood mononuclear cells (PBMCs) at weeks 2, 8, and 14
• Trough serum TEV-48574 concentrations throughout the study (sparse sampling)
• Population pharmacokinetic parameters (eg, clearance, volume of the central compartment, area under the concentration-time curve, maximum observed drug concentration, and trough drug concentration)
• Population pharmacokinetic-PD parameter
• Exposure-response parameters
• Primary and other efficacy endpoints |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 96 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Moldova, Republic of |
| Ukraine |
| Canada |
| Georgia |
| Israel |
| Japan |
| Serbia |
| South Africa |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Bulgaria |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Norway |
| Poland |
| Slovakia |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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