| 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] - Immune System Diseases [C20] |
| 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 evaluate the efficacy of a treat to target strategy coupled with early endoscopic assessment versus a clinically driven (routine care) approach in achieving endoscopic response. |
|
| E.2.2 | Secondary objectives of the trial |
- To examine the robustness of the primary endpoint analysis, sensitivity analyses of the primary endpoint will be conducted.
- To evaluate the efficacy of a treat to target strategy coupled with early endoscopic assessment versus a clinically driven approach in achieving endoscopic remission.
- To evaluate the efficacy of a treat to target strategy coupled with early endoscopic assessment versus a clinically driven approach in achieving mucosal healing.
- To evaluate the efficacy of a treat to target strategy coupled with early endoscopic assessment versus a clinically driven approach in achieving clinical remission.
- To evaluate the efficacy of a treat to target strategy coupled with early endoscopic assessment versus a clinically driven approach in achieving clinical response.
Please see pages 22/23 of the protocol for an overall overview of the secondary objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male or female ≥18 years of age
2) Have active moderate to severe, ileal and/or colonic Crohn’s disease demonstrated by:
Baseline CDAI score of ≥220 and ≤450,
and...
...Endoscopy with evidence of active Crohn’s disease (defined as SES-CD score ≥3 excluding the contribution of the narrowing component score) obtained within the 5-week screening period. A prior endoscopy may be used only if obtained within 3 months prior to baseline (Week 0), in which case the prior endoscopy must be centrally read again and SES-CD calculated based on this second, centralized read-out.
3) Has had an inadequate response with, lost response to, was intolerant to, or had medical contraindications to either:
•conventional therapy, or
•one previous biologic therapy approved for the treatment of Crohn’s disease in the countries in which the study is conducted.
4) Adhere to the following requirements for concomitant medication for the treatment of Crohn’s disease.
5) Are eligible according to tuberculosis (TB) infection screening criteria
6) Must sign an informed consent form (ICF) (or their legally acceptable representative if applicable must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study
7) A woman of childbearing potential must have a negative highly sensitive serum pregnancy test at screening, and a negative urine pregnancy test at Week 0.
8) Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.
9) A woman must agree not to donate eggs for the purposes of assisted reproduction during the study and for 15 weeks after the last study drug administration.
10) During the study and for 15 weeks after receiving the last dose of study drug, in addition to a highly effective method of contraception, a man
- who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception
- must agree not to donate sperm.
11) Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
|
|
| E.4 | Principal exclusion criteria |
1)Has complications of Crohn’s disease such as symptomatic strictures or stenoses, short gut syndrome, or any other manifestation that might be anticipated to require surgery,could preclude the use of the CDAI to assess response to therapy, or would possibly confound the ability to assess the effect of treatment with ustekinumab.
2) Currently has or is suspected to have an abscess. Recent cutaneous and perianal abscesses are not exclusionary if drained and adequately treated at least 3 weeks prior to baseline, or 8 weeks prior to baseline for intra-abdominal abscesses, provided there is no anticipated need for any further surgery.
Subjects with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses identified.
3) Has had any kind of bowel resection within 6 months prior to baseline.
4) Has a draining stoma or ostomy.
5) Has received more than one previous biologic therapy approved for the treatment of Crohn’s disease in the countries in which the study is conducted.
6) Has previously received a biologic agent targeting IL-12 and/or IL-23, including but not limited to ustekinumab.
7) Has received any of the following prescribed medications or therapies within the specified period:
a. IV corticosteroids <3 weeks prior to baseline.
b. Other oral immunomodulatory agents <6 weeks prior to baseline.
c. Non-autologous stem cell therapy or biologic agents that deplete B or T cells
d. Vedolizumab <12 weeks prior to baseline.
e. Anti-TNF biologic agents or other agents intended to suppress or eliminate TNF <8 weeks prior to baseline.
f. Any investigational drug within 4 weeks before first administration of study drug or within 5 half-lives of the investigational drug, whichever is longer.
g. Treatment with apheresis or total parenteral nutrition as a treatment for
Crohn’s disease <3 weeks prior to baseline.
8) Has received a Bacille Calmette-Guérin vaccination within 12 months or any other live bacterial or live viral vaccination within 12 weeks of baseline.
9) Have a stool culture or other examination positive for an enteric pathogen, including Clostridium difficile toxin, in the last 4 months unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen.
10) Has a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection, recurrent urinary tract infection, or open, draining, or infected skin wounds or ulcers.
11) Has current signs or symptoms of infection. Established nonserious infections need not be considered exclusionary at the discretion of the investigator.
12) Has a history of serious infection, including any infection requiring hospitalization or IV antibiotics, for 8 weeks prior to baseline.
13) Has evidence of a herpes zoster infection ≤8 weeks prior to baseline.
14) Has a history of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, prior to screening.
15) Has evidence of current active infection, including TB, or a nodule suspicious for lung malignancy on screening or any other available chest radiograph, unless definitively resolved surgically or by additional imaging and with source document confirmation.
16) Has or ever has had a nontuberculous mycobacterial infection or serious opportunistic infection
17) Is known to be infected with HIV, hepatitis B, or hepatitis C.
18) Has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof.
19) Has a transplanted organ >12 weeks prior to screening.
20) Has a known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
21) Has any known malignancy or has a history of malignancy
22) Has previously undergone allergy immunotherapy for prevention of anaphylactic reactions.
23) Has known allergies, hypersensitivity, or intolerance to ustekinumab or its excipients or an allergy to latex
24) is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 15 weeks after the last dose of study drug
25) is a man who plans to father a child while enrolled in this study or within 15 weeks after the last dose of study drug.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Endoscopic response at Week 48, defined as showing (yes or no) a reduction from baseline in simple endoscopic score for Crohn’s disease (SES-CD) of ≥50%. Randomized subjects who stop treatment before reaching Week 48 due to any reason, or subjects without endoscopic data at Week 48 will be analyzed as nonresponders. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Endoscopic response at Week 48, defined as showing (yes or no) a reduction from baseline in SES-CD score of ≥50%. Randomized subjects who stop treatment before reaching Week 48 due to reasons other than lack/loss of efficacy will be excluded from the analysis.
- Endoscopic response defined as a reduction from baseline in SES-CD score of ≥50% at endpoint (LOCF)
- Endoscopic remission defined as a SES-CD score ≤2 at Week 48 and endpoint (LOCF)
- Mucosal healing defined as the complete absence of mucosal ulcerations in any ileocolonic
segment at Week 48 and endpoint (LOCF)
- Clinical remission defined as a CDAI score of <150 points.
- Clinical response defined as a ≥100 point reduction from the baseline CDAI score, or a CDAI score <150
- Corticosteroid-free clinical remission
- Corticosteroid-free endoscopic response (endoscopic response defined as a reduction from baseline in SES-CD score of ≥50%)
- Serum CRP
- FC
- Percentage of subjects with a 16-point change from baseline for Inflammatory bowel disease
questionnaire (IBDQ)
- Percentage of subjects with a 7-point change from baseline in work productivity and activity impairment (WPAI) scores for each domain |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 |
| comparison between routine care and treat to target |
|
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 105 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 10 |
| 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 | 10 |
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