| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A chronic inflammatory bowel disease that affects the lining of the digestive tract |
|
| 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 |
| The primary objective is to evaluate the achievement of clinical response at Week 16 following a single intravenous (IV) re-induction dose of ~6 milligram per kilogram (mg/kg) ustekinumab, compared with continuing regular subcutaneous (SC) dosing every 8 weeks (q8w) 90 milligram (mg) ustekinumab administration, in participants with secondary loss of response (LoR) to SC q8w 90 mg ustekinumab maintenance therapy. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to:
● Evaluate the achievement of clinical response and clinical remission, as well as the reduction in inflammatory biomarkers (serum C-reactive protein [CRP] and fecal calprotectin [FCal] levels), after IV ustekinumab re-induction.
● Assess the overall safety of IV ustekinumab re-induction. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential participant must satisfy all the following criteria to be enrolled in the study:
1. Male or female aged ≥18 years (or the legal age of consent in the jurisdiction in which the study is taking place if older than 18 years).
2. A history of Crohn’s disease or fistulizing Crohn’s disease of at least 3 months’ duration, with colitis, ileitis, or ileocolitis, confirmed at any time in the past by radiography, histology, and/or endoscopy.
3. Initially responded to ustekinumab induction therapy (a), administered according to the local label, followed by secondary LoR to ustekinumab (b).
a) Initial response to ustekinumab as defined in Section 10.2.
b) Secondary LoR to ustekinumab is defined as active disease at study baseline, proven by a crohn’s disease activity index (CDAI) score of ≥220 and ≤450 with at least one of the following:
- Elevated CRP (>3.0 milligram per litre [mg/L]); and/or
- Elevated FCal (>250 mg/kg); and/or
- Endoscopy (performed ≤ 3 months before baseline) with evidence of active Crohn’s disease (defined as one or more ulcerations in the ileum and/or colon).
Participants must currently be on a SC 90mg ustekinumab q8w maintenance dose regimen and have received at least 2 doses of SC 90
mg ustekinumab treatment 8 weeks apart prior to enrollment
4. The following medications for the treatment of Crohn’s disease are permitted providing the doses indicated are stable for at least 3 weeks before baseline or have been discontinued at least 3 weeks before baseline:
● Oral 5-aminosalicylic acid (5-ASA) compounds.
● Oral corticosteroids (eg, prednisone, budesonide) at a prednisone-equivalent dose of ≤40 mg/day or ≤9 mg/day of budesonide.
● Antibiotics used as the primary treatment of Crohn’s disease.
Any participants receiving conventional immunomodulators (ie, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) must have been taking them for ≥12 weeks and must have been on a stable dose for a least 4 weeks before baseline.
5. The following laboratory test results are within the specified limits at screening:
● Hemoglobin ≥8.5 g/dL (≥85 g/L).
● White blood cell (WBC) count ≥3.5 x 10^3/µL (≥3.5 GI/L).
● Neutrophils ≥1.5 x 10^3/µL (≥1.5 GI/L).
● Platelets ≥100 x 10^3/µL (≥100 GI/L).
● Serum creatinine <1.7 mg/dL (≤150 μmol/L).
● Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase levels ≤2 times the upper limit of normal for the laboratory conducting the test.
● Direct (conjugated) bilirubin <1.0 mg/dL (<0.01 g/L).
6. Meet the following TB screening criteria:
● No history of latent or active TB before screening. An exception is made for participants who have a history of latent TB and are currently receiving treatment for latent TB, will initiate treatment for latent TB prior to first administration of study intervention, or have documentation of having completed appropriate treatment for latent TB within 5 years prior to the first administration of study intervention. It is the responsibility of the investigator to verify the adequacy of previous TB treatment and provide appropriate documentation.
● No signs or symptoms suggestive of active TB upon medical history and/or physical examination.
● No recent close contact with a person with active TB. If there has been such contact, the participant will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, will receive appropriate treatment for latent TB prior to or simultaneously with the first administration of study intervention.
● Meets all other protocol-specified TB inclusion criteria
8. All female participants of childbearing potential must have a negative highly sensitive serum (-human chorionic gonadotropin [-hCG]) pregnancy test at screening and a negative urine pregnancy test at baseline and prior to each administration of study intervention.
9. A male participant who is heterosexually active with a woman of childbearing potential and is not surgically sterile must agree to use a double-barrier method of birth control and not donate sperm during the study and for 15 weeks after receiving study intervention.
11. Sign an informed consent document indicating that he/she understands the purpose of and procedures required for the study and is willing to participate in the study.
Please see protocol for an overview of all inclusion criteria |
|
| E.4 | Principal exclusion criteria |
1.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 before baseline, or 8 weeks before baseline for intra-abdominal abscesses, provided there is no anticipated need for any further surgery. Participants with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses identified.
3.Any kind of bowel resection within 6 months or any other intra-abdominal surgery within 3 months before baseline.
4.A draining (ie, functioning) stoma or ostomy.
5.Received any of the following prescribed medications or therapies within the specified period:
● Use of IV ustekinumab re-induction after the initial weight-tiered based IV induction dose of ustekinumab
● Any known history of shortened frequency of SC dose administration for a secondary loss of response where the participant did not, in the opinion of the treating physician, benefit from the dose interval shortening.
●Any off-label use of ustekinumab, including additional IV re-induction or shortened frequency of subcutaneous dose administration, after the initial weight-tiered based IV induction dose of ustekinumab.
●Intravenous corticosteroids as a treatment for Crohn’s disease within 3 weeks before baseline.
●Oral immunomodulatory agents other than AZA, 6-MP, or MTX within 4 weeks before baseline.
●Any other investigational agent for Crohn’s disease, unless at least 3 months or 5 half-lives have elapsed since the last dose.
●Treatment with apheresis or total parenteral nutrition as a treatment for Crohn’s disease within 3 weeks before baseline.
6.A stool culture or other examination in the last 4 months that is positive for an enteric pathogen, including Clostridium difficile toxin, unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen.
7.Received a Bacille Calmette-Guérin vaccination within 12 months before baseline or any other live bacterial or live viral vaccination within 2 weeks before baseline.
8.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.
9.Any current signs or symptoms of infection. Established non-serious infections need not be considered exclusionary at the discretion of the investigator.
10.A history of serious infection, including any infection requiring hospitalization or IV antibiotics, for 8 weeks before baseline.
11.Evidence of a herpes zoster infection ≤8 weeks before baseline.
12.A history of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, before screening; refer to Inclusion Criterion 6 for information regarding eligibility with a history of latent TB.
13.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.
14.A current or (lifetime) history of a nontuberculous mycobacterial infection or serious opportunistic infection
15.Known to be infected with human immunodeficiency virus, hepatitis B, or hepatitis C.
16.Severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or any signs or symptoms thereof.
17.A transplanted organ, with the exception of a corneal transplant performed >12 weeks before screening.
18.A known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
19.Any known malignancy or a history of malignancy, with the exception of: basal cell carcinoma; squamous cell carcinoma in situ of the skin; cervical carcinoma in situ that has been treated with no evidence of recurrence; or squamous cell carcinoma of the skin that was treated with no evidence of recurrence within 5 years before screening.
20.Previous allergy immunotherapy for prevention of anaphylactic reactions.
21.Unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins.
Please see protocol for an overview of all exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is clinical response at Week 16, defined as a ≥100-point reduction from the baseline CDAI score or a CDAI score <150 points. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Clinical remission at Week 16, defined as a CDAI score of <150 points.
2. Clinical response at Week 8, defined as a ≥100-point reduction from the baseline CDAI score or a CDAI score <150.
3. Clinical remission at Week 8, defined as a CDAI score of <150 points.
4. Normalization of CRP and/or FCal concentration(s) at Week 16, among participants with an elevated CRP and/or FCal at baseline.
5. Clinical remission at Week 24, defined as a CDAI score of <150 points.
6. Clinical response at Week 24, defined as a ≥100-point reduction from the baseline CDAI score or a CDAI score <150.
7. Normalization of CRP and/or FCal concentration(s) at Week 24, among participants with an elevated CRP and/or FCal at baseline.
8. Safety endpoints, including the proportion of participants with at least one adverse event and subcategories of adverse events (all infections, all serious adverse events and serious infections), as well as changes in clinical laboratory test results. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 & 4. At week 16
2 & 3. At week 8
5, 6 & 7. At week 24
8. Throughout the study (Screening to week 24 or early termination) |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| 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 |
| Korea, Republic of |
| Russian Federation |
| United States |
| Austria |
| Czechia |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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