| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to Severely Active Crohn’s Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011401 |
| E.1.2 | Term | Crohn's disease |
| 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 demonstrate superiority of CT-P13 SC over Placebo SC based on clinical remission and endoscopic response at Week 54. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate additional efficacy, PK, pharmacodynamics (PD), usability, and overall safety including immunogenicity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female aged 18 to 75 years, inclusive.
2. Patient who has moderately to severely active CD with a score on the CDAI of 220 to 450 points at Screening.
3. Patient with average (of 7 days) daily stool frequency ≥4 points (of Type 6 or Type 7 on the BSFS and/or an average (of 7 days) worst daily abdominal pain of ≥2 points (using 4 point scale) at Screening.
4. Patient who has a SES CD of ≥6 points for ileal-colonic CD or ≥4 points including ulcer score from at least 1 segment for ileal CD or colonic CD at Screening.
5. Patient who has CD, confirmed at any time in the past by radiography, histology, or endoscopy, of at least 3 months’ disease duration prior to the first administration of the study drug (Day 0).
6. Patient who has been treated for active CD but has not responded despite a full and adequate course of therapy with corticosteroids and/or immunosuppressants; or who is intolerant to or has medical contraindications for such therapies.
7. Patient who is receiving a stable dose of the following CD treatments or currently not receiving CD treatment during the specified time frame:
• Azathioprine (AZA), 6-mercaptopurine (6-MP) or Methotrexate (MTX) for at least 8 weeks prior to the first administration of the study drug (Day 0)
• Oral corticosteroids at the equivalent dose of 20 mg/day or less of prednisone for at least 2 weeks prior to the first administration of the study drug (Day 0)
• Oral budesonide at a dose of 9 mg/day (if the country specific dosage is approved for CD treatment) or 6 mg/day or less for at least 4 weeks prior to the first administration of the study drug (Day 0)
• 5-Aminosalicylates (5-ASA) or antibiotics (i.e., ciprofloxacin, metronidazole) for at least 4 weeks prior to the first administration of the study drug (Day 0)
8. Patient who has adequate renal and hepatic function at Screening as defined by the following clinical chemistry results:
• Serum creatinine <1.5×upper limit of normal (ULN) or an estimated creatinine clearance level >50 mL/min (by Cockcroft-Gault formula)
• Serum alanine aminotransferase <2.5×ULN
• Serum aspartate aminotransferase <2.5×ULN
• Serum total bilirubin <2×ULN
9. Patient who has the following clinical hematology results at Screening:
• Hemoglobin ≥8.5 g/dL (SI [Système International d'Unités] units: ≥85 g/L or 5.28 mmol/L)
• White blood cell count ≥3.5×103 cells/µL (SI units: ≥3.5×109 cells/L)
• Neutrophil count ≥1.5×103 cells/µL (SI units: ≥1.5×109 cells/L)
• Platelet count ≥100×103 cells/µL (SI units: ≥100×109 cells/L)
10. Patient (or legal guardian, if applicable) who is informed of the full nature and purpose of the study, including possible risks and side effects, has the ability to cooperate with the investigator and is given ample time and opportunity to read or understand verbal and/or written instructions, and has signed and dated the written informed consent form (ICF) prior to participation in the study.
11. For both male and female patients, the patient and his or her partner of childbearing potential who agree to use one of the following medically acceptable methods of contraception during the course of the study and for 6 months following discontinuation of study drug (excluding women who are not of childbearing potential and men who have been sterilized):
• Barrier contraceptives (male condom, female condom, or diaphragm with a spermicidal gel)
• Hormonal contraceptives (implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings)
• Intrauterine device
Male and female patients and their partners who have been surgically sterilized for less than 6 months prior to the date of informed consent must agree to use any of the medically acceptable methods of contraception. Menopausal females must have experienced their last period more than 12 months prior to the date of informed consent to be classified as not of childbearing potential. |
|
| E.4 | Principal exclusion criteria |
1. Patient who has previously received 2 or more biologic agents, 2 or
more Janus kinase (JAK) inhibitors, or 2 or more of both biologic agents
and JAK inhibitors
2. Patient who has previously received either a TNFα inhibitor or
biological agent within 5 half-lives prior to the first administration of the
study drug (Day 0).
3. Patient who has previously demonstrated inadequate response or
intolerance to TNFα inhibitors for the treatment of CD.
4 Patient who has previously received infliximab for treatment of CD or other disease.
5. Patient who has allergies to any of the excipients of infliximab or anyother murine and/or human proteins, or has a hypersensitivity to
immunoglobulin products.
6. Patient who has received or has a plan to receive any of following
prohibited medications or treatments:
• Parenteral corticosteroids for the treatment of CD within 2 weeks prior
to the first administration of the study drug (Day 0), JAK inhibitors
including but not limited to tofacitinib and baricitinib within 4 weeks
prior to the first administration of the study drug (Day 0), Alkylating
agents within 12 months prior to the first administration of the study
drug (Day 0), Cyclosporine, tacrolimus, sirolimus, or mycophenolate
mofetil within 8 weeks prior to the first administration of the study drug
(Day 0), Live or live-attenuated vaccine within 4 weeks prior to the first
administration of the study drug (Day 0), Abdominal surgery for,
including but not limited to, active gastrointestinal bleeding, peritonitis,
intestinal obstruction, GI resection or intra abdominal or pancreatic
abscess requiring surgical drainage within 6 months prior to the first
administration of the study drug (Day 0), Nonautologous stem cell
therapy (e.g., Prochymal) within 12 months prior to the first
administration of the study drug (Day 0), Apheresis for the treatment ofCD within 3 weeks prior to the first administration of the study drug
(Day 0), Use of total parenteral nutrition within a month prior to the
first administration of the study drug (Day 0), Use of exclusive enteral
nutrition for more than 3 consecutive days within a month or any single day of exclusive enteral nutrition within 2 weeks prior to the first administration of the study drug (Day 0)
7. Patient who has a current or history of any of the following infections: Known infection with hepatitis B or hepatitis C (active or carrier state), or infection with HIV. However, a patient who is without cirrhosis of liver and recovered from a past hepatitis B or hepatitis C infection can be enrolled. In case of hepatitis C infection, patient who has achieved a SVR for at least 12 weeks after completing the treatment for hepatitis C infection can be enrolled. Acute infection requiring oral antibiotics within 2 weeks or parenteral injection of antibiotics within 4 weeks prior to the first administration of the study drug (Day 0); Other serious infection, in the investigator's opinion, within 6 months prior to the first administration of the study drug (Day 0);Recurrent herpes zoster or other chronic or recurrent infection, in the investigator's opinion, within 6 weeks prior to the first administration of the study drug (Day 0);Past
or current granulomatous infections or opportunistic infections; Evidence of infection with cytomegalovirus within 6 months prior to the first administration of the study drug (Day 0); Evidence of Clostridium difficile toxin within 3 months prior to the first administration of the study drug (Day 0); Positive stool examinations for enteric pathogens, pathogenic ova or parasites at Screening
8. Patient who has a medical condition including 1 or more of the
following:
Diagnosed with UC or indeterminate colitis; Extensive colonic resection (subtotal and total colectomy) prior to the first administration of the study drug (Day 0); History of more than 3 small-bowel resection procedures prior to the first administration of the study drug (Day 0);
Diagnosed with short bowel syndrome; Evidence of fixed symptomatic
stenosis or obstruction of the large or small intestine
Currently require or are anticipated to require surgical intervention for
CD during the study; Active entero-vesical, entero-retroperitoneal,
entero-cutaneous, or entero-vaginal fistulae within 6 months prior to the first administration of the study drug (Day 0). Entero-enteral fistulae without clinically significant symptoms in the investigator's opinion and anal fistulae without draining problems are allowed;
Stoma (e.g., ileostomy or colostomy) within 6 months prior to the first
administration of the study drug (Day 0); Body mass index ≥35 kg/m2;
Uncontrolled diabetes mellitus, even after insulin treatment;
Uncontrolled hypertension (as defined by systolic blood pressure ≥160
mmHg or diastolic blood pressure ≥100 mmHg)
For remaining details about exclusion criteria, please refer to the
protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Clinical remission at Week 54, defined as an absolute CDAI score of <150 points
• Endoscopic response at Week 54, defined as a 50% decrease in SES-CD score from the baseline value
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endopoint evaluation will be conducted at Week 54. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary endpoints: CDAI-100 response at Week 54, defined as a decrease in CDAI score of 100 points or more from the baseline value; Clinical remission at Week 54, defined as an average worst daily abdominal pain score of ≤ 1 (using 4-point scale), and an average loose/watery stool frequency score of ≤ 3 (of Type 6 or Type 7 on BSFS) with no worsening in either score compared to the baseline value; Corticosteroid-free remission at Week 54, defined as being in clinical remission (by an absolute CDAI score of <150) in addition to not receiving oral corticosteroid for at least 8 weeks prior to Week 54,
among the patients who used oral corticosteroids at baseline; Endoscopic remission at Week 54, defined as an absolute SES-CD score of ≤ 4 and at least 2-point reduction from the baseline value with no
sub-score of >1
Other Secondary endpoints: Clinical remission, defined as an absolute CDAI score of <150 points; Maintenance of clinical remission at Week
54, defined as being in clinical remission by CDAI score of <150 points, among the patients in clinical remission at Week 10; Sustained clinical
remission at both Week 22 and Week 54, defined as an average worst daily abdominal pain score of ≤1 (using 4-point scale), and an average loose/watery stool frequency score of ≤3 (of Type 6 or Type 7 on BSFS) at both Week 22 and Week 54 with no worsening in either score compared to the baseline value; CDAI-70 response, defined as a
decrease in CDAI score of 70 points or more from the baseline value; CDAI-100 response, defined as a decrease in CDAI score of 100 points or more from the baseline value; Maintenance of clinical response at Week 54, defined as being in CDAI- 100 response at Week 54, among the patients in CDAI-100 response at Week 10; Sustained clinical response
at both Week 22 and Week 54, defined as a reduction from the baseline value in average worst daily abdominal pain score (using 4-point scale),
and/or in average daily loose/watery stool frequency (of Type 6 or Type 7 on BSFS) at both Week 22 and Week 54; Endoscopic remission, defined as an absolute SES-CD score of ≤4 and at least 2-point reduction from the baseline value with no sub-score of >1; Endoscopic response, defined as a 50% decrease in SES-CD score from the baseline value;
Patient global scale, defined as a question that asks a patient's position on achieving remission from his or her CD symptoms (Yes or No); Short
Inflammatory Bowel Disease Questionnaire (SIBDQ)
PK Assessments: For all patients, Ctrough will be assessed up to Week 100 and Cmax will be assessed at Week 6. Blood samples for PK analysis
will be collected at pre-dose (prior to the beginning of study drug administration) of Weeks 0, 2, 6, 10, 14, 22, 30, 38, 46, 54, 62, 70, 78, 86, 94, 102 and within 15 minutes after the end of the study drug
infusion of Week 6. On the day of initiation of dose adjustment, blood samples for PK analysis will be collected at pre-dose.
Usability Assessments: The following Usability endpoints for PFS or AI will be assessed only for self-injected patients: Usability for PFS assessed by patient rating using PRE- and POST Self- Injection
Assessment Questionnaire (SIAQ) at Weeks 14, 16, 18, 20, and 22.
Usability for AI as assessed by patient rating using PRE- and POSTSIAQ at Weeks 56, 58, 60, and 62.The observer rating of successful self injection
for PFS, indicated by complete dose delivery, using P8, P9, and P10 of the Self-Injection Assessment Checklist at Weeks14 and 22. The observer rating of successful self-injection for AI, indicated by complete
dose delivery, using P8, P9, P10, and P11 of the Self-Injection Assessment Checklist at Weeks 56 and 62. The observer rating of completion of all instructions in the Self-Injection Assessment Checklist for PFS at Weeks 14 and 22. The observer rating of completion of all instructions in the Self-Injection Assessment Checklist for AI at Weeks 56 and 62. Device integrity for used PFS at Weeks 14 and 22. Device integrity for used AI at Weeks 56 and 62.
Safety assessments will be performed on immunogenicity, hypersensitivity monitoring, vital sign measurements, weight, 12-lead ECGs, monitoring of TB signs and symptoms, monitoring of
cardiovascular disease related signs and symptoms, chest X ray, IGRA, hepatitis B and C and HIV-1 and -2 status, NYHA functional classification
assessment, diabetes mellitus, stool microbiology, physical examination findings, AEs, AEs of special interest (infusion-related reaction/systemic
injection reaction, infection, delayed hypersensitivity, localized injection site reaction, malignancy), monitoring of drug-induced liver injury,
pregnancy testing, clinical laboratory analyses, local site pain using 100 mm Visual Analogue Scale, and prior and concomitant medications. In case of delayed hypersensitivity including serum sickness-like reactions, Immunogenicity; Clinical laboratory analyses; Complement (C3, C4) and total hemolytic complement |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Key secondary endopoints evaluations will be conducted at Week 54 and other secondary endopoints evaluations will be conducted at time points described in protocol. PK, PD and safety assessments will be perfored at the time points specificed in the schedule of events (Table 10-1 and 10-2). |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| 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 | 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 106 |
| 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 |
| Belarus |
| Brazil |
| Chile |
| Georgia |
| India |
| Israel |
| Japan |
| Mexico |
| Moldova, Republic of |
| Peru |
| Russian Federation |
| Serbia |
| South Africa |
| Turkey |
| Ukraine |
| United States |
| Bulgaria |
| Croatia |
| Estonia |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Latvia |
| Poland |
| Portugal |
| Romania |
| Slovakia |
| Spain |
| Czechia |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 3 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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