| 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 |
| Inflammatory bowel disease (IBD) |
|
| 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 JNJ-64304500 to reduce the CDAI score from baseline.
- To evaluate the safety of JNJ-64304500. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of JNJ-64304500 to induce clinical remission, clinical response, and endoscopic healing of the mucosa, and to maintain remission
- To evaluate the relationship between efficacy and the presence of the NKG2D and/or MICB SNP biomarkers.
- To evaluate the efficacy of JNJ-64304500 to improve general and disease-specific healthrelated quality of life and to reduce Crohn’s disease-related hospitalizations and surgeries.
- To evaluate the pharmacokinetics, immunogenicity, pharmacodynamics, and biomarkers (eg, reductions in CRP, fecal calprotectin, and fecal lactoferrin) of JNJ-64304500 therapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Have 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.
- Have active Crohn’s disease, defined as a baseline CDAI score of ≥220 but ≤450.
Have at least one of the following at screening: An abnormal CRP (>0.3 mg/dL [>3.0 mg/L]) OR Calprotectin >250 mg/kg.
Study 1: Has previously demonstrated inadequate response, loss of response, or intolerance to 1 or more approved biologic therapies
Study 2: Has failed conventional therapy (currently receiving corticosteroids and/or immunomodulators OR has a history of failure to respond to or tolerate an adequate course of corticosteroids and/or immunomodulators OR is corticosteroid dependent or has had a history of corticosteroid dependency).
Part II: Has previously demonstrated inadequate response, loss of response, or intolerance to 1 or more approved biologic therapies or has failed conventional therapy.
All 3 Studies:
- Adhere to the following requirements for concomitant medication for the treatment of Crohn's disease, which are permitted provided that doses meeting these requirements are stable, or have been discontinued, for at least 3 weeks before baseline (Week 0), unless otherwise specified:
a. Oral 5-aminosalicylic acid (5-ASA) compounds.
b. Oral corticosteroids at a prednisone-equivalent dose at or below 40 mg/day, or 9 mg/day of budesonide, or 5 mg/day beclomethasone dipropionate.
c. Antibiotics being used as a primary treatment of Crohn's disease.
d. Conventional immunomodulators (ie, AZA, 6-MP, or MTX): subjects must have been taking them for at least 12 weeks and at a stable dose for at least 4 weeks before baseline.
- A subject with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age >50 years, or other known risk factor must be up-to-date on colorectal cancer surveillance
- A subject who has had extensive colitis for ≥8 years, or disease limited to the left side of the colon for ≥12 years, must either have had a colonoscopy to assess for the presence of dysplasia within 1 year before the first administration of study agent or a colonoscopy to assess for the presence of malignancy at the screening visit, with no evidence of malignancy.
- Have screening laboratory test results within the following parameters:
a. Hemoglobin ≥8.0 g/dL.
b. White blood cell count ≥3.0 × 103/μL.
c. Neutrophils ≥1.5 × 103/μL.
d. Platelets ≥100 × 103/μL.
e. Serum creatinine <1.7 mg/dL.
f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations must be within 2 times the upper limit of the normal (ULN) range for the laboratory conducting the test.
g. Direct (conjugated) bilirubin <1.0 mg/dL.
- Are considered eligible according to the following tuberculosis (TB) screening criteria (see details in protocol):
a. Have no history of latent or active TB before screening.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c. Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB before or simultaneously with the first administration of study agent.
d. Within 2 months before the first administration of study agent, either have negative QuantiFERON-TB test, or have a newly identified positive QuantiFERON-TB test in which active TB has been ruled out, and for which appropriate treatment for latent TB has been initiated either before or simultaneously with the first administration of study agent
e. Have a chest radiograph (posterior-anterior and lateral views), taken within 3 month before the first administration of study agent and read by a qualified radiologist, with no evidence of current active TB or old inactive TB.
- A woman of childbearing potential must have a negative highly sensitive serum (β-human chorionic gonadotropin [β-hCG]) pregnancy test result at screening and a negative urine pregnancy test result at Week 0.
- Before randomization, a female subject must be either:
a. Not of childbearing potential or
b. Of childbearing potential and:
1) Practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly), consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. If using a hormone birth control method, a second method of birth control, such as a condom or
diaphragm, must be used.
2) Agrees to remain on a highly effective method of contraception throughout the study and for at least 16 weeks after the last administration of study agent. |
|
| 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, or would possibly confound the ability to assess the effect of treatment with JNJ-64304500 or ustekinumab.
2 Currently has or is suspected to have an abscess (see details in protocol).
3 Has had any kind of bowel resection within 6 months or any other intra-abdominal surgery within 3 months before baseline.
4 Has a draining (ie, functioning) stoma or ostomy.
5 Has received any of the following prescribed medications or therapies within the specified period:
a IV corticosteroids
b Other oral immunomodulatory agents (eg, 6-thioguanine [6-TG], cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil, tofacitinib and other Janus kinase [JAK] inhibitors)
c Nonbiologic experimental or investigational agents
d Nonautologous stem cell therapy (eg, Prochymal), natalizumab, efalizumab, or biologic agents that deplete B or T cells (eg, rituximab, alemtuzumab, or visilizumab)
e TNFα-antagonist biologic agents (eg, mAb therapies) or other agents intended to suppress or eliminate TNFα
f Vedolizumab
g Other immunomodulatory biologic agents
h Treatment with apheresis (eg, Adacolumn apheresis)
i Initiation of total or partial parenteral nutrition administered through any indwelling catheter or anticipated to require parenteral nutrition administered through an indwelling catheter during enrollment in the study
j Initiation of enteral therapy for Crohn’s disease (liquid nutritional formula comprising ≥80% of total caloric intake administered through the gastrointestinal tract). Subjects who are on a stable regimen of enteral feeds may be considered for enrollment if they plan to continue enteral feeds as treatment for Crohn’s disease.
6 Has a stool culture or other examination positive for an enteric pathogen in the last 4 months unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen.
7 Has previously received a biologic agent targeting IL-12 or IL-23
8 Has previously received JNJ-64304500 or NNC0142-002
9 Has received a Bacille Calmette-Guérin (BCG) vaccination within 12 months or any other live bacterial or live viral vaccination within 12 weeks before baseline
10 Has a history of, or ongoing, chronic or recurrent infectious disease
11 Has current signs or symptoms of infection. Established nonserious infections (eg, acute upper respiratory tract infection, simple urinary tract infection) need not be considered exclusionary at the discretion of the investigator
12 Has a history of serious infection (eg, sepsis, pneumonia, or pyelonephritis)
13 Has evidence of a Herpes zoster infection
14 Has a history of latent or active granulomatous infection before 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
16 Has or ever has had a nontuberculous mycobacterial infection or serious opportunistic infection
17 Has a history of HIV antibody positivity, or tests positive for HIV at screening
18 Are seropositive for antibodies to HCV without a history of successful treatment
19 Subjects must undergo screening for HBV:
a Subjects who test negative for all HBV screening tests (ie, HBsAg-, anti-HBc-, and anti-HBs-) are eligible for this study
b Subjects who test positive for surface antigen (HBsAg+) are not eligible for this study, regardless of the results of other hepatitis B tests
c Subjects who test negative for surface antigen (HBsAg-) and test positive for core antibody (anti-HBc+) and surface antibody (anti-HBs+) are eligible for this study
d Subjects who test positive only for surface antibody (anti-HBs+) are eligible for this study
e Subjects who test positive only for core antibody (anti-HBc+) must undergo further testing for hepatitis B DNA acid (HBV DNA test). If the HBV DNA test is positive, the subject is not eligible for this study. If the HBV DNA test is negative, the subject is eligible for this study. In the event the HBV DNA test cannot be performed, the subject is not eligible for this study.
20 Has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof
21 Has a transplanted organ (with exception of a corneal transplant >12 weeks before screening)
22 Has a known history of lymphoproliferative disease, including monoclonal gammopathy of unknown significance (MGUS), lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly
23 Has any known malignancy or has a history of malignancy
24 Is unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part I: Change from baseline in the CDAI score at Week 8
Part II: Change from baseline in the CDAI score at Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part I: Week 8
Part II: Week 12 |
|
| E.5.2 | Secondary end point(s) |
The following endpoints will be evaluated as major secondary endpoints only in Part II (the dose-ranging portion of the study); these endpoints will be evaluated in Part I, but are not specified as major secondary endpoints.
1. Clinical remission at Week 12 as measured by CDAI (CDAI <150).
2. Clinical response at Week 12 as measured by CDAI (≥100-point reduction from baseline in CDAI or CDAI <150).
3. Change in PRO-2 (the sum of the abdominal pain and stool frequency subscores of the CDAI score) from baseline at Week 12.
4. Clinical remission at Week 12 as measured by PRO-2 (PRO-2 <75).
5. Clinical response at Week 12 as measured by PRO-2 (≥50-point reduction from baseline in PRO-2 or PRO-2 <75).
6. Change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline at Week 12.
The following efficacy endpoints will be evaluated in Part I and Part II:
7. Change in abdominal pain score (mean daily average based on the CDAI assessment) from baseline at all postbaseline visits.
8. Change in stool frequency score (mean daily average based on the CDAI assessment) from baseline at all postbaseline visits.
9. Change in CDAI from baseline at all postbaseline visits.
10. Clinical remission based on CDAI at all postbaseline visits.
11. Clinical response based on CDAI at all postbaseline visits.
12. Change in PRO-2 from baseline at all postbaseline visits.
13. Clinical remission based on PRO-2 at all postbaseline visits.
14. Clinical response based on PRO-2 at all postbaseline visits.
15. Change in PRO-3 (the sum of abdominal pain, stool frequency, and general well-being subscores of the CDAI score) from baseline at all postbaseline visits.
16. Clinical remission based on CDAI at Week 24 among subjects in clinical response at Week 12.
17. Clinical remission based on CDAI at Week 24 among subjects in clinical remission at Week 12.
For further endpoints see protocol. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoints 1. - 6.: At week 12
Endpoints 7. - 15.: At all postbaseline visits
Endpoints 16.-17.: At week 24
|
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 99 |
| 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 |
| Belgium |
| Bulgaria |
| Canada |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Romania |
| Russian Federation |
| Ukraine |
| United Kingdom |
| United States |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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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