The primary objective is to evaluate the achievement of clinical response at Week 16 following a single IV re-induction dose of *6 mg/kg ustekinumab, compared with continuing regular SC q8w 90 mg ustekinumab administration, in participants with…
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Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective is to evaluate the achievement of clinical response at
Week 16 following a single IV re-induction dose of *6 mg/kg ustekinumab,
compared with continuing regular SC q8w 90 mg ustekinumab administration, in
participants with secondary loss of response (LoR) to SC q8w 90 mg ustekinumab
maintenance therapy.
Secondary outcome
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.
Background summary
The study hypothesis is that in patients with secondary LoR to SC q8w 90 mg
ustekinumab maintenance treatment, a single weight-tiered based
IV ustekinumab re-induction dose of *6 mg/kg (ie, IV
ustekinumab/SC placebo at Week 0) followed by q8w 90 mg ustekinumab maintenance
will result in a higher clinical response rate (defined as a >=100-point
reduction from the baseline CDAI score, or a CDAI score <150) compared with
continuous SC q8w 90 mg ustekinumab maintenance treatment (ie, IV
placebo/SC ustekinumab at Week 0) after 16 weeks.
Study objective
The primary objective is to evaluate the achievement of clinical response at
Week 16 following a single IV re-induction dose of *6 mg/kg ustekinumab,
compared with continuing regular SC q8w 90 mg ustekinumab administration, in
participants with secondary loss of response (LoR) to SC q8w 90 mg ustekinumab
maintenance therapy.
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.
The exploratory objectives are to assess endoscopy and patient-reported
assessment of bowel inflammation following IV ustekinumab re-induction, and
to assess the steroid-sparing effect and pharmacokinetics following a single IV
re-induction dose of *6 mg/kg ustekinumab.
Study design
This is a randomized, double-blind, placebo-controlled, multicenter, 24-week,
Phase 3b study in adult patients with active moderate to severe Crohn*s disease
who initially responded (as defined in Section 10.2, Appendix 2 of the
protocol) to ustekinumab induction therapy per label followed, at any time, by
secondary LoR to SC q8w ustekinumab maintenance therapy. The benefit of a
single weight- tiered based IV re-induction dose of *6 mg/kg body weight
ustekinumab versus continuous SC q8w maintenance treatment will be evaluated.
Secondary LoR is defined as a CDAI score of >=220 and <=450 plus at least one of
the following:
* Elevated CRP (>3.0 mg/L); and/or
* Elevated FCal (>250 mg/kg); and/or
* Endoscopy (ileocolonoscopy) with evidence of active Crohn*s disease during
the current disease flare (ie, ulcerations in the ileum and/or colon).
Eligible participants will be randomly assigned to 1 of the following 2
re-induction groups in a 1:1 ratio, using permuted block randomization
stratified at the study level by participant*s baseline CDAI score (<=300 or
>300) and prior biologic failure (yes or no) at baseline.
* Ustekinumab re-induction: IV ustekinumab and SC placebo at Week 0.
* Continuous maintenance: IV placebo and SC ustekinumab at Week 0.
At baseline (Week 0), approximately 8 weeks (±2 weeks) after the previous per
label dose of SC 90 mg ustekinumab maintenance, participants will undergo
clinical assessments. Following randomization, participants will receive IV
ustekinumab *6 mg/kg and SC placebo or IV placebo and SC ustekinumab 90 mg in
a double-blind manner.
At study visits at Weeks 8 and 16, all participants will receive SC ustekinumab
90 mg and will undergo clinical assessments, including ileocolonoscopy at Week
16.
At Week 24, all participants will undergo study assessments before resuming
their standard of care at the discretion of the treating physician. All
participants will also have a follow-up for evaluation of safety at Week 36,
which may be conducted at a site visit or by telephone.
Key efficacy assessments will include clinical response (CDAI reduction >=100),
clinical remission (CDAI value <150) and biomarker normalization. Safety
assessments will include the monitoring of adverse events, vital signs, and
clinical laboratory tests.
Intervention
Study intervention will start at baseline (Week 0), approximately 8 weeks (±2
weeks) after the previous dose of per label SC 90 mg ustekinumab maintenance
treatment. The date of the previous dose of ustekinumab will be recorded in the
case report form (CRF).
To maintain the double-blind, all participants will receive one IV injection of
study intervention (ustekinumab *6 mg/kg or placebo) plus one SC administration
of study intervention (ustekinumab 90 mg or placebo) at Week 0.
At Weeks 8 and 16, all participants will receive SC maintenance injections of
90 mg ustekinumab. Following study assessments at Week 24, all participants
will resume their standard-of-care therapy with either ustekinumab maintenance
therapy per label (SC 90 mg ustekinumab at this visit and q8w thereafter) or
another treatment modality at the discretion of their physician.
Study burden and risks
The expected therapeutic effect justifies the burden and risks for the
participants.
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Listed location countries
Age
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 within the 3 months
before baseline) with evidence of active Crohn*s disease during the current
disease flare (ie, 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 90mg 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
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:, *Any known history of
shortened frequency of SC dose administration (response where the participant did not, in the opinion of treating physician,
benefit from the dose interval shortening *Use of IV ustekinumab re-induction
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
(eg, Janus kinase [JAK] inhibitors, 6-thioguanine [6-TG], cyclosporine,
tacrolimus, sirolimus, tofacitinib, or mycophenolate mofetil) within 4 weeks
before baseline., *Any other investigational agent for Crohn*s disease (eg
other biologics, small molecules or anti-sense RNA such as mongersen), unless
at least 3 months or 5 half-lives (whichever is longer) have elapsed since the
last dose., *Treatment with apheresis (eg, Adacolumn 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 (BCG) 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
(eg, recurrent pyelonephritis or chronic nonremitting cystitis), or open,
draining, or infected skin wounds or ulcers., 9.Any current signs or symptoms
of infection. Established non-serious infections (eg, acute upper respiratory
tract infection, simple urinary tract infection) need not be considered
exclusionary at the discretion of the investigator., 10.A history of serious
infection (eg, sepsis, pneumonia, or pyelonephritis), 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 (eg, Cytomegalovirus
colitis, Pneumocystis carinii, aspergillosis)., 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
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 | EUCTR2018-002629-51-NL |
| CCMO | NL67051.091.18 |