| 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 | | To evaluate the efficacy and dose response of 2 different maintenance dose regimens of TEV-48574 subcutaneous (sc) administered every 4 weeks (Q4W) in adult patients with IBD (moderate to severe UC or CD) as assessed by clinical remission (UC) and endoscopic response (CD) at end of treatment (EOT) | |
| E.2.2 | Secondary objectives of the trial | During the maintenance period: to evaluate the efficacy of 2 different maintenance dose regimens of TEV-48574 sc administered Q4W in adult patients with IBD (moderate to severe UC or CD) as assessed by multiple standard measures at EOT.
Other:
- to evaluate the safety and tolerability of 2 different maintenance dose regimens of TEV-48574
- to evaluate the immunogenicity of 2 different maintenance dose regimens of TEV-48574
- to evaluate the safety and tolerability of 2 re-induction doses
The maintenance period includes some exploratory objectives.
During the re-induction period: to evaluate the safety and tolerability of 2 re-induction doses of TEV-48574 sc administered every 2 weeks (Q2W) in adult patients with IBD (moderate to severe UC or CD). The re-induction period includes some exploratory objectives too.
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Maintenance period: a. Adults of male and female sex (without restrictions on gender) who at the time of informed consent achieved clinical response and/or clinical remission at week 14 of TV48574-IMM-20036 (the 14-week DRF study) or in the re-induction period of this study.
- Clinical response assessed by decrease from baseline in modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score by ≥2 points and at least 30%, with a decrease in rectal bleeding subscore of ≥1 point or an absolute subscore of 0 or 1 at week 14 of the of the TV48574-IMM-20036 DRF study in patients with moderate to severe UC .
- Clinical remission at week 14 of the DRF study/re-induction period 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”
- Clinical response assessed by ≥100-point decrease CDAI score from DRF study baseline week 14 of the TV48574-IMM-20036 DRF study/re-induction period in patients with moderate to severe CD
- Clinical remission defined as a CDAI score <150 at week 14 of the DRF study/re-induction period in patients with moderate to severe CD
2. Re-induction: Adults of male and female sex (without restrictions based on gender) who did not achieve clinical response and/or clinical remission at week 14 of the TV48574 IMM 20036 DRF study
b. Patients who are women of childbearing potential (WOCBP) should have a negative β- human chorionic gonadotropin test result and practice a highly effective method of birth control.
• Male patients (including vasectomized) with WOCBP partners should use condoms after the first IMP administration and throughout the study
c. The patient must be willing and able to comply with study restrictions and to remain at the investigational center for the required duration during the study period, and willing to return to the investigational center for further visits, as applicable, and the follow-up procedures and assessments as specified in this protocol | |
| E.4 | Principal exclusion criteria | a. Patients who discontinued the TV48574-IMM-20036 DRF study before scheduled week 14 visit (any reason including lack of efficacy, safety, or personal reasons) and patients who didn’t meet the definition of clinical response or clinical remission based on their DRF week 14 assessment
b. 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.
c. Diagnosis of indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis.
d. 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.
e. 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 study visit.
f. Patient anticipates requiring major surgery during this study.
g. A history of an opportunistic infection (eg, CMV retinitis, Pneumocystis carinii, or aspergillosis).
h. A history of more than 2 herpes zoster episodes in the last 5 years or multimetameric herpes zoster.
i. A history of or ongoing chronic or recurrent serious infectious disease (eg, infected indwelling prosthesis or osteomyelitis).
j. Current or history of chronic liver or biliary disease (with the exception of Gilbert’ syndrome, asymptomatic gallstones or uncomplicated fatty liver disease) at screening or baseline ALT or AST >2x ULN or bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at week 14 of the DRF study or the re-induction period.
k. Absolute neutrophil count <1.5x109/L or Hemoglobin <8 g/dL or lymphocyte count <0.8x109/L or platelet count <100,000/mL at week
14 of the DRF study or the re-induction period. If a subject fails to meet an exclusion laboratory criterion due to an isolated laboratory test
falling outside of the normal acceptable range, a single retest will be permitted once, with the retest value determining subject eligibility for the study.
l. The patient has QTc>480 ms at week 14 of the DRF study or the re induction period. If a subject fails to meet an exclusion criterion due to
an isolated electrocardiogram (ECG) reading falling outside of the normal acceptable range, a single retest will be permitted once, with the retest determining subject eligibility for the study..
m. m. Any acute infection that in the opinion of the investigator compromises the safety of the patients .
n. 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.
o. The patient has a known hypersensitivity to the IMP and/or excipients.
p. Presence of a transplanted organ.
q. 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).
r. Patient has or is receiving any of the following therapies during the DRF study and/or within the transition period from the DRF study to the LTE study
- The patient is currently using any systemic immunosuppressant or
immunomodulatory biologic or nonbiologic except AZA, 6-MP, MTX
- >9 mg/day of oral budesonide or >20 mg/day prednisone or equivalent
- Topical (rectal) treatment of 5-aminosalicylic acid (5-ASA) or intravenous, intramuscular (parenteral), or enema/suppository administration of corticosteroids
- Biologics including anti-TNF, anti-integrins, and anti-interleukin (IL-) 12/23 inhibitors or anti IL-23
- Small molecules including janus kinase (JAK) inhibitors, or sphingosine-1- phosphate (S1P) receptor modulators
- Other investigational procedures or products excluding IMP
- Live vaccine. Inactivated vaccines (including approved inactivated coronavirus disease 2019) 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
s. Current or history (within 2 years) of serious psychiatric disease or alcohol or drug abuse
t. Patients with incurable diseases, persons in nursing homes, and patients incapable of giving informed written consent | |
| E.5 End points |
| E.5.1 | Primary end point(s) | During the maintenance period:
-Clinical remission based on modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score of ≤2 points defined by a
stool frequency subscore of 0 or 1, rectal bleeding subscore of 0, and an endoscopic subscore of 0 or 1, where a score of 1 does not include “friability” at week 24 in patients with UC
- Endoscopic response, defined as a decrease in Simple Endoscopic Score
for Crohn's Disease (SES-CD) of > 50% from DRF study baseline at week
24 in patients with CD | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | During the maintenance period the secondary efficacy endpoints are as follows:
- Clinical response, based on modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score of at least 2 points AND at
least a 30% reduction from DRF study 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 at week 44 in patients with UC
- Endoscopic improvement from DRF study baseline based on Mayo endoscopic subscore of 0 or 1 at week 44 in patients with UC
- Endoscopic remission based on Mayo endoscopic subscore of 0 at week 44 in patients with UC
- Corticosteroid-free clinical remission based on the modified Mayo score
at week 44, defined by clinical remission (see primary endpoint) and corticosteroid-free for =12 weeks preceding week 44, in patients with
UC
- Clinical response based on Crohn's Disease Activity Index (CDAI): ≥100-point decrease in CDAI score from DRF study baseline in patients
with CD at week 44
- Clinical remission based on CDAI score <150 at week 44 in patients with CD
- Corticosteroid-free endoscopic response based on SES-CD at week 44, defined by endoscopic response (see primary endpoint) and corticosteroid-free for =12 weeks preceding week 44, in patients with CD
- Corticosteroid-free clinical remission based on CDAI at week 44, defined by a CDAI score of <150 points and corticosteroid-free for =12 weeks preceding week 44, in patients with CD
Other secondary endpoints include:
Safety and tolerability measures/parameters as follows:
- Patients who stopped the IMP due to adverse events
- Frequency of adverse events
- Potentially clinically significant laboratory test results (serum chemistry, hematology, and urinalysis)
- Potentially clinically significant vital signs measurements (blood pressure, pulse rate, body temperature, and respiratory rate)
- Potentially clinically significant 12-lead electrocardiogram (ECG) findings
- Local tolerability at the injection site
Immunogenicity endpoints as follows:
- Treatment-emergent anti-drug antibody (ADA) results and responses: change from baseline (DRF study) and throughout the study
- Neutralizing ADA in ADA positive patients throughout the study.
- Impact of the presence of ADAs on pharmacokinetics and clinical safety will be assessed if applicable
During the re-induction period the secondary endpoint includes the safety and tolerability measure/parameter adverse event. The study includes exploratory endpoints too for the maintenance and re-induction period. | |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description | | The tested drug given at one dose is compared to a different dose of the same product. | |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 6 |
| 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 | | Canada | | Georgia | | Israel | | 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
