A *treat to target* strategy has been advocated as an optimized management approach for various diseases, by which strictly defined treatment targets facilitate decision making in clinical practice. Key to the success of this treatment strategy is…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
-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 (routine care) approach in
achieving endoscopic remission.
-To evaluate the efficacy of a treat to target strategy coupled with early
endoscopic assessment versus a clinically driven (routine care) approach in
achieving mucosal healing.
-To evaluate the efficacy of a treat to target strategy coupled with early
endoscopic assessment versus a clinically driven (routine care) approach in
achieving clinical remission.
-To evaluate the efficacy of a treat to target strategy coupled with early
endoscopic assessment versus a clinically driven (routine care) approach in
achieving clinical response.
-To evaluate the efficacy of a treat to target strategy coupled with early
endoscopic assessment versus a clinically driven (routine care) approach in
eliminating the need for corticosteroids while maintaining disease control.
-To evaluate the effect of a treat to target strategy coupled with early
endoscopic assessment versus a clinically driven (routine care) approach on
serum CRP and FC levels.
-To evaluate the effect of a treat to target strategy coupled with early
endoscopic assessment versus a clinically driven (routine care) approach on
health-related quality of life (QoL), patient-reported outcomes and
pharmacoeconomics.
Background summary
Ustekinumab is a fully human immunoglobulin G1 kappa (IgG1k) monoclonal
antibody to human IL-12/23p40 that binds with high affinity to the p40 subunit
of human IL-12 and IL-23. By inhibiting interaction with the cell surface
IL-12R*1 receptor protein, ustekinumab effectively neutralizes all IL-12 (Th1)
and IL-23 (Th17) mediated cellular responses. Abnormal regulation of IL-12 and
IL-23 has been associated with multiple immune- mediated diseases including
Crohn*s disease.
Ustekinumab (STELARA®) has been approved by the EMA for the treatment of
moderate to severe plaque psoriasis in adults or adolescent patients, and for
the treatment of active psoriatic arthritis. At the time of protocol writing,
ustekinumab has positive opinion from the CHMP at
the EMA, and approval from the United States Food and Drug Administration for
the treatment of adult patients with moderately to severely active Crohn*s
disease who have had an inadequate response with, lost response to, were
intolerant to, or have medical contraindications to either:
conventional therapy, or TNF* antagonist therapy.
Inflammatory bowel diseases (IBD) are chronic, progressive, and disabling
conditions. Most current strategies, which target control of symptoms, do not
appear to significantly alter the natural course of the disease. Recent studies
in Crohn*s disease underscore the need to look beyond symptoms and to treat
endoscopic/macroscopic lesions, ultimately with the aim of preventing
structural damage and disability. Due to the invasive nature and/or cost of
endoscopies or cross-sectional imaging, frequent repetition of these procedures
is not feasible; STELARA (ustekinumab) therefore, surrogate biomarkers of
inflammation, including CRP and fecal calprotectin (FC) have been increasingly
studied in IBD.
Study objective
A *treat to target* strategy has been advocated as an optimized management
approach for various diseases, by which strictly defined treatment targets
facilitate decision making in clinical practice. Key to the success of this
treatment strategy is the definition of appropriate treatment targets and
adoption of algorithms that drive therapeutic changes within distinct time
frames. This approach has been shown to be successful in chronic,
immune-mediated inflammatory disorders such as rheumatoid arthritis and
psoriatic arthritis. Recently, the value of such an approach in patients*
management has been suggested for IBD.
The goal of this study of adult Crohn*s disease subjects treated with
ustekinumab is to demonstrate that a maintenance strategy based on early
endoscopy followed by regular assessment of biomarkers (FC and CRP) and
clinical symptoms (CDAI) with subsequent adjustment of treatment in case of
persistent inflammatory disease activity (failure to achieve the target) is
more successful in achieving endoscopic improvement than a pragmatic
maintenance strategy based on guidance provided in the EU SmPC for the use of
ustekinumab in Crohn*s disease.
Study design
This is a randomized, open-label, parallel-group, multicenter, multinational,
Phase 3b interventional study of ustekinumab in adult subjects with active
moderate to severe Crohn*s disease. The benefit of a treat to target
maintenance treatment strategy versus routine care will be investigated. For
the treat to target strategy, ustekinumab treatment will be adjusted based on
the regular assessment of disease activity by objective clinical and biological
outcome measures and clinical symptoms. Maintenance treatment in the routine
care arm will be pragmatic, in compliance with the EU SmPC for ustekinumab in
Crohn*s disease.
A target of 650 adult male and female subjects with endoscopic evidence of
active disease will be enrolled. Subjects enrolled will have previously had an
inadequate response with, lost response to, been 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. Study subjects may be biologic-naïve or
biologic-experienced, having received no more than one prior biologic approved
for the treatment of Crohn*s disease.
During a screening period of up to 5 weeks, eligibility of subjects will be
evaluated, and centrally-read endoscopic assessments at screening will be used
for baseline evaluation. At Week 0, all eligible subjects will initiate
intravenous (IV) induction treatment with ustekinumab, in line with the EU
SmPC, on a weight-tiered basis at a dose of approximately 6 mg/kg IV. At Week
8, all subjects will receive a 90 mg SC injection of ustekinumab.
At Week 16, subjects who do not achieve a CDAI improvement of 70 points versus
Week 0 (CDAI-70) will leave the study. Subjects who remain in the study will be
randomized in a 1:1 ratio to either one of two arms for open-label maintenance
treatment up to Week 48: the treat to target arm or the routine care arm.
Randomized subjects will be stratified according to whether biologic-naïve at
baseline versus prior exposure to 1 biologic for the treatment of Crohn*s
disease, and according to baseline SES-CD score *16 or SES-CD >16.
In the routine care arm, assessment visits will be scheduled according to the
timing of maintenance treatment injections, which will be in compliance with
the EU SmPC for ustekinumab for the treatment of Crohn*s disease, in which
dosing every 12 weeks is recommended. At Week 16, (ie, 8 weeks after the first
SC dose), subjects who have not shown adequate response based on the
investigator*s judgment may
receive a second SC dose at that time. During the routine care maintenance
treatment period, clinical assessments in case of disease flare will be at the
investigator*s discretion. Consistent with the EU SmPC for ustekinumab,
subjects who lose response during 12-weekly dosing may benefit from an
adjustment to 8-weekly maintenance treatment. Subjects may subsequently be
dosed every 8 weeks or every 12 weeks according to clinical judgment. In
contrast, those subjects previously receiving 8-weekly treatment will not be
able to adjust the ustekinumab dose following disease flare and will leave the
study if they would not benefit from continuing study treatment in the
investigator*s judgment.
In the treat to target arm, initial ustekinumab maintenance treatment
assignment will be based on centrally-read ileocolonoscopy findings. Subjects
with <25% improvement in SES-CD score at Week 16 versus baseline will be
assigned to 8-weekly maintenance treatment. Subjects with *25% improvement in
SES-CD score at Week 16 versus baseline will be assigned to 12-weekly
treatment. Subsequently, at assessment visits (from Week 24 for subjects
assigned to the 8-weekly regimen or from Week 20 for the 12-weekly group)
ustekinumab maintenance treatment will be directed by treat to target
assessments. The treatment target will be the achievement of either:
- CDAI <220 and a CDAI-70 response (defined as a 70-point improvement in CDAI
score from baseline)
AND:
- CRP *10 mg/L or FC *250 *g/g.
For subjects who do not have elevated CRP at baseline (ie, CRP *2.87 mg/L at
Week 0) in the presence of active disease, CRP would not be considered a
biomarker target for dose adjustment
Subjects meeting the treatment target will continue on the same ustekinumab
dosing frequency. Maintenance dosing frequency will be optimized for subjects
failing to meet the treatment targets: those subjects previously on 12-weekly
regimens will be adjusted to 8-weekly dosing; those previously on 8-weekly
regimens will be adjusted to 4-weekly dosing. Subjects subsequently failing to
meet treatment targets at the next assessment visit 4 weeks after dosing will
not be able to optimize dosing further and will leave the study. In case of
disease flare between scheduled assessment visits for the treat to target arm,
subjects will undergo CDAI and biomarker (CRP and FC) assessments. Dosing
frequency will be adjusted for subjects failing to meet the treatment target.
All subjects will have study visits at Weeks 0, 8 and 16, at each assessment
visit at the times scheduled for study drug administration, and at Week 48. In
cases of disease flare arising between scheduled study visits, subjects in both
arms will also be assessed at the time of disease flare. A final
ileocolonoscopic assessment will be performed at the Week 48 study visit.
Subjects discontinuing treatment before Week 48 will have an early termination
visit at the time of discontinuation, unless consent is withdrawn.
Early termination assessments should include an ileocolonoscopic assessment.
Subjects will be allowed to enter the study on oral corticosteroids at a
prednisone-equivalent dose of *40 mg/day or *9 mg/day of budesonide. For
subjects receiving corticosteroids who are randomized at Week 16 (CDAI-70
responders) corticosteroid tapering is mandatory. A recommended corticosteroid
tapering schedule is specified in the protocol. Corticosteroid tapering can be
initiated from Week 8 in subjects already demonstrating response (CDAI-70) to
ustekinumab treatment.
From Week 48, subjects will continue ustekinumab treatment in the study
extension period, up to Week 104. The frequency of dosing will be based on
endoscopic and/or clinical remission at Week 48, and subsequently on clinical
remission and biomarker findings.
For all subjects, final safety follow-up assessments will be performed 16 weeks
after the last administration of ustekinumab within the study. For subjects
completing the 104-week study and moving to commercially-available ustekinumab,
final safety follow-up assessments should be performed before the first dose of
commercially-available drug. The study will be considered completed with the
last visit for the last subject participating in the study.
Intervention
At Week 0, all eligible subjects will initiate intravenous (IV) induction
treatment with ustekinumab, on a weight-tiered basis at a dose of approximately
6 mg/kg IV. At Week 8, all subjects will receive a 90 mg SC injection of
ustekinumab.
At Week 16, subjects who do not achieve a CDAI improvement of 70 points versus
Week 0 (CDAI-70) will leave the study. Subjects who remain in the study will be
randomized in a 1:1 ratio to either one of two arms for open-label maintenance
treatment up to Week 48: the treat to target arm or the routine care arm.
In the routine care arm, assessment visits will be scheduled according to the
timing of maintenance
treatment injections (every 8 or 12 weeks) based on the investigator*s
judgment. Subjects previously receiving 8-weekly treatment will not be able to
adjust the ustekinumab dose following disease flare and will leave the study if
they would not benefit from continuing study treatment in the investigator*s
judgment.
In the treat to target arm, initial ustekinumab maintenance treatment
assignment will be based on centrally-read ileocolonoscopy findings (every 8 or
12 weeks).Subsequently, at assessment visits (from Week 24 for subjects
assigned to the 8-weekly regimen or from Week 20 for the 12-weekly group)
ustekinumab maintenance treatment will be directed by treat to target
assessments. The treatment target will be the achievement of either:
- CDAI <220 and a CDAI-70 response (defined as a 70-point improvement in CDAI
score from baseline)
AND:
- CRP *10 mg/L or FC *250 *g/g.
For subjects who do not have elevated CRP at baseline (ie, CRP *2.87 mg/L at
Week 0) in the presence of active disease, CRP would not be considered a
biomarker target for dose adjustment
subjects previously on 12-weekly regimens will be adjusted to 8-weekly dosing;
those previously on 8-weekly regimens will be adjusted to 4-weekly dosing.
Subjects subsequently failing to meet treatment targets at the next assessment
visit 4 weeks after dosing will not be able to optimize dosing further and will
leave the study.
From Week 48, subjects will continue ustekinumab treatment in the study
extension period, up to Week 104. The frequency of dosing will be based on
endoscopic and/or clinical remission at Week 48, and subsequently on clinical
remission and biomarker findings.
Study burden and risks
For side effects of Ustekinumab, I refer to the Informed consent form.
Side effects related to procedures:
Blood draw: Taking blood may cause bruising at the place where the needle goes
into the skin. Fainting, and in rare cases infection, may occur.
X-Ray Risks: The radiation dose that is in the x-ray(s) taken for this study is
small. There is no significant risk from this amount of radiation.
ECG Risk: There is generally no risk with having an ECG. The sticky patches may
pull your skin or cause redness or itching.
Ileocolonoscopy: A long, flexible, tube is inserted through the rectum into the
colon up to the last part of the ileum. The doctor will explain this in more
detail before the procedure is performed and will also explain possible risks
and discomforts for these in more detail.
Abdominal ultrasound:An ultrasound scanning device consists of computer and a
transducer that is used to scan the body. A transducer is a small hand-held
device about the size of a bar of soap that is attached to the scanner by a
cord. A lubricating gel is spread on the skin over the area being examined, and
then the transducer is pressed firmly against the skin to obtain images.The
doctor will explain this in more detail before the procedure is performed and
will also explain possible risks and discomforts for these in more detail.
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Listed location countries
Age
Inclusion criteria
1) Male or female *18 years of age;2) Have active moderate to severe Crohn*s disease;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.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002918-43-NL |
| CCMO | NL60565.056.17 |