To evaluate the effects of AMT-101 in combination with adalimumab on UC disease activity as measured by symptoms, endoscopy, histology, and biomarkers. To evaluate the safety and tolerability of oral AMT-101 over 8 weeksTo assess the PK parameters…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Mean change in UC-100 score from baseline
Mean change in Robarts Histopathology Index (RHI) from baseline
• Mean change in total Mayo Clinic Score (MCS) and component scores (Mayo
Endoscopic Subscore [MES], partial MCS, rectal bleeding, and stool frequency)
from baseline
• Mean change in faecal calprotectin from baseline
• Mean change in highly sensitive C-reactive protein value (hs-CRP) from
baseline
• Endoscopic remission rate (defined as an MES of 0 or 1)
• Endoscopic response rate (defined as a decrease in MES of at least 1 point
from baseline)
• Mucosal healing (defined as MES of 0 or 1 and a Geboes histological index
score of <= 3.1)
• Histological remission rate (defined as Geboes histological index score of <=
2B.0; or Robart's histopathology index [RHI] <= 3 with a subscore of 0 for
lamina propria neutrophils and 0 for neutrophils in the epithelium)
• Percentage of subjects with a 50% decrease in RHI • Clinical remission rate
(defined as total MCS <= 2 with all subscores <= 1)
• Clinical response rate (defined as a decrease in MCS of at least 3 points and
at least 30% from baseline, with a decrease in rectal bleeding subscore of at
least 1 point or an absolute rectal bleeding subscore of 0 or 1)
• Clinical remission rate (alternate definition of the Mayo subscore for bowel
movement frequency of 0 or 1 and Mayo subscore for rectal bleeding of 0 and MES
of 0 or 1)
Security endpoints
• Frequency and severity of side effects
• Changes from baseline in clinical chemistry and hematology
• Changes from baseline in vital signs and physical exams
• Electrocardiogram (ECG) findings
Secondary outcome
Exploratory endpoints
• Levels of AMT-101, AMT-101 anti-drug antibodies (ADAs), total interleukin-10
(IL-10), adalimumab, and adalimumab ADAs in serum
• Concentrations of AMT-101, AMT-101 ADAs and total IL-10 in mucosal tissue
biopsies
• Mean change on the Symptoms and Impact questionnaire for UC (SIQ-UC) from
baseline
• Mean change in inflammatory bowel disease questionnaire score from baseline
• Change in the number of white blood cells
• Change in faecal matrix metalloproteinase 9 (MMP-9)
• Change in faecal lactoferrin
• Change in interleukin-1 receptor antagonist (IL-1Ra)
• Change in protein content in serum and mucosal tissue • Change in gene
expression in the mucosa
• Change in cell populations in the mucosa
• Change in the faecal microbiome
Background summary
Disease Background:
Inflammatory Bowel Disease (IBD) is an autoimmune disease of the
gastrointestinal (GI) tract with unknown etiology that encompasses 2 primary
clinical manifestations: ulcerative colitis (UC) and Crohn*s disease (CD). IBD
affects over 1.5 million people in North America and as many as 2.5 million in
Europe, with a growing global spread and a prevalence of up to 0.5% of the
population in most impacted regions.
UC manifests through complex interactions between the gut microbiome,
dysregulated immune responses, genetic mutations, diet, and other environmental
factors. As a result, the precise etiology for disease initiation differs
widely among patients with UC. The incidences of UC in European countries range
from 0.9 to 24.3 per 100,000 person-years. The highest incidence rates are
observed in Scandinavia and the United Kingdom, while the lowest rates are seen
in Southern and Eastern Europe. Extrapolation of the incidence figures on the
total European population (approximately 731 million in 2006) indicate a
maximal estimate 178,000 cases of UC each year. The prevalence of UC in
European countries varies from 2.4 to 294 cases per 100,000 persons; it is
estimated that 2.1 million persons are in total are afflicted with UC in
Europe.
Current therapies for UC are modestly successful and have significant adverse
side effects including systemic immunosuppression, increased incidence of
opportunistic and rare infections, and increased risk for cancer. Furthermore,
approximately half of UC patients will relapse in any given year, including a
minority with frequently relapsing or chronic, continuous disease. Prognosis in
UC remains generally optimistic, but 15.6 % will undergo surgery within 10
years of diagnosis, with 20% to 30% of patients ultimately proceeding to
surgical colectomy. In addition, UC may have a profound effect on quality of
life, including mental health consequences, and a significant minority become
incapable of work due to disease. Thus, there remains a significant and unmet
clinical need to better manage UC with safer and more effective oral therapies.
Study Drug Background:
AMT-101(cholix386-polyGlyser-rhIL-10) is a homodimeric fusion protein where
each monomer consists of a cholix386 domain and a recombinant human interleukin
(IL) -10 (rhIL-10) domain connected by a 14 amino acid polypeptide spacer of
glycine and serine residues. The cholix386 domain of AMT-101 is a truncated
form of cholix protein, a nontoxic mutant derived from Vibrio cholerae. The
cholix386 domain facilitates active transport of AMT-101 across epithelial
cells to the local GI submucosal tissue.
IL-10 is an immunomodulatory cytokine that inhibits effector functions of
activated macrophages and monocytes in vitro, down-regulates the production of
proinflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-α], IL-1β and
IL-6 from macrophages and interferon (IFN)-γ and IL-2 from T-cells) and
cytokine receptor expression (e.g., TNF receptor [TNF-r]), and upregulates
cytokine inhibitors (e.g., soluble TNF-r and IL-1Ra). IL-10 effects are
mediated through activation of the januse kinase (JAK)/signal transducer and
activator of transcription 3 (STAT3) signaling cascade, where phosphorylated
STAT3 homodimers translocate to the nucleus to activate the expression of
target genes. Activation of STAT3 in epithelial cells has been reported to
promote cellular protection, survival and proliferation.
Parenterally-administered rhIL-10 has been evaluated in clinical trials
conducted by other sponsors with IBD and while generally safe and
well-tolerated did not result in significantly reduced remission rates or
clinical improvements when compared to placebo.
AMT-101 is formulated as an enteric-coated tablet intended for oral
administration, resulting in targeted, gut-restricted delivery and uptake, with
low systemic exposure. Local delivery of IL-10 may bypass the side effects
experienced with systemic administration and is expected to translate into
higher mucosal concentrations and clinically meaningful reductions in
inflammation and disease activity.
Rationale for the Study
Rationale for the use of AMT-101 in the treatment of IBD and UC is based on
several studies in animal models and humans. Nonclinical studies with AMT-101
in rodents using oral gavage administration and monkeys using pan-colonic
administration (via the rectum) have demonstrated both localization of AMT- 101
in intestinal submucosal tissue and activation of STAT3 by phosphorylation.
Oral AMT-101 has shown evidence of anti-inflammatory activity in relevant
animal models of IBD.
The rationale for evaluating the combination of AMT-101 with anti-TNF therapy
is based on recent data suggesting that anti-TNF treatment response depends on
IL-10 signaling pathways. In this series of experiments, the response to
anti-TNF therapy in a mouse T-cell transfer model of colitis was reduced by
pharmacological inhibition of IL 10, and this was found to be mediated by
macrophages and not T-cells. Furthermore, in a small sample of patients with
CD, different patterns of IL-10 production from human monocytes and mucosal
mRNA expression of IL-10 and related cytokines were observed between responders
and nonresponders to anti-TNF therapy. Therefore, it has been proposed that
defects in IL-10 pathways may at least partially explain why some patients do
not respond to anti-TNF therapy and that response to anti-TNF therapy may be
partially IL-10 dependent. Approximately one-third of patients may exhibit
nonresponse. It is hypothesized that addition of AMT-101 may improve response
to anti-TNF therapy in patients with IBD through activation of IL-10 signaling
pathways.
Based on the preliminary results of the Phase 1 study, the dose selected for
this study (3 mg administered once daily) is expected to be safe, well
tolerated, and result in pharmacological effects in intestinal tissue in
subjects with UC. The study is designed with a 8-week induction period because
this is typical for IBD treatments and is expected to be of adequate duration
to demonstrate clinical effects; previous Phase 2 studies of other treatments
have employed 8 to 12 weeks of induction. Nonclinical toxicology studies are
currently ongoing to evaluate longer periods of AMT-101 administration, and
potentially support maintenance dosing regimens in the future.
Study objective
To evaluate the effects of AMT-101 in combination with adalimumab on UC disease
activity as measured by symptoms, endoscopy, histology, and biomarkers.
To evaluate the safety and tolerability of oral AMT-101 over 8 weeks
To assess the PK parameters of AMT-101 in combination with adalimumab
To assess health-related quality of life (HRQOL)
To assess the PD effect of AMT-101 on biomarkers
To assess target engagement and mechanism of action
Study design
This is a randomized, placebo-controlled, double-blind, parallel-group,
multicenter study. As this is a proof-of-concept study, the objectives and
endpoints are descriptive and designed to explore multiple types of outcomes,
including clinical, endoscopic, histologic, PK, PD, and HRQOL.
Endoscopic assessments will be scored both locally and centrally and histologic
assessments will be scored centrally. Study central readers will receive
standardized training on Robarts* Central Image Management Solutions (CIMS) for
assessment of endoscopy and histopathology (qualified gastroenterologists and
pathologists, respectively). Central readers will enter scores in a study
database. For endoscopic assessments, central reader scores will be the primary
scores for analyses and for confirming eligibility. In the case of adjudication
for endoscopy, the second central reader (adjudicator) would select either the
local reader or first central reader score to be used as the final score
(forced adjudication). For histologic assessments, there will be a single
central read.
A total of 30 subjects with moderate to severe UC (total MCS 6-12; MES >= 2) are
planned to be enrolled in this study from approximately 4 centers in Europe.
Eligible subjects will be randomized in a 1:1 ratio to receive adalimumab +
placebo or adalimumab + AMT-101 (3 mg). Adalimumab will be administered by
subcutaneous injection according to the induction regimen outlined on the
product label. AMT-101 or matching placebo will be administered orally, once
daily for 8 weeks.
Intervention
Both groups are treated with adalimumab for 8 weeks, per standard dose as
prescribed
1 group takes 1 tablet of AMT-101 once a day. The other group takes 1 placebo
tablet once a day
Study burden and risks
Nonclinical studies evaluating AMT-101 support the mechanism of action for
targeted, intestinally restricted delivery of rhIL-10 via oral administration,
while minimizing systemic IL-10 exposure. The nonclinical effects of AMT-101
have been studied in a comprehensive panel of studies that address
pharmacology, pharmacodynamics, pharmacokinetics and toxicology, including
evaluation of AMT-101 in two mouse models of disease. There were no adverse
effects at the highest dose tested in repeat-dose toxicology studies up to 13
weeks. Results from the AMT-101 nonclinical program indicates a potential
therapeutic benefit of an oral targeted delivery rhIL-10 in the management of
ulcerative colitis, pouchitis and potentially other related diseases.
Initial clinical evaluation of oral AMT-101 in a first-in-human clinical study
in healthy subjects and patients with active UC, suggests that AMT-101 is
generally well tolerated, with all treatment emergent AEs being mild (Grade 1)
to moderate (Grade 2) in severity. Preliminary data from this ongoing clinical
study supports the hypothesis that AMT-101 treatment has potential for clinical
activity in patients.
Taken together, the AMT-101 nonclinical program and clinical experience with
oral AMT-101, supports a favorable projected risk-benefit profile for the
continued clinical development of AMT-101 as a monotherapy and in combination
with other modalities of IBD treatment in Phase 2 trials for UC and pouchitis.
Clinical reproductive toxicity risk of AMT-101 is unknown. Nonclinical
reproductive toxicity studies have not been completed and no clinical
pregnancies have been observed. Histopathology of the reproductive tract was
evaluated as part of repeat-dose toxicology testing and no test-article-related
effects were observed. To minimize risk, women planning to become pregnant are
not eligible for the study, study subjects must agree to use contraception, and
pregnancy tests will be performed throughout the study.
Risks associated with study procedures/tests:
- Blood samples: Pain, bruising and/or bleeding where the needle enters the
vein. Some people feel light-headed or faint. Rarely will this procedure lead
to swelling and/or infection of the vein.
- Sigmoidoscopy: Cramping, pain, abdominal bloating (common). Peritonitis
(inflammation of the lining of the abdominal cavity) (rare). Perforation (a
hole) of the intestinal wall (rare). Surgery may be needed if a perforation
occurs (rare).
- Video capture sigmoidoscopy: No discomfort/risk is expected from the video
capture. Video images are identified by study identification number. There is a
chance that the video images may accidentally lead to identification however,
such disclosure is not planned or expected.
- Intestinal biopsy: Persistent bleeding after biopsy or polyp removal (if
taken) can occur. Biopsy results can identify a cancer of the intestine (bowel).
- Stool sample: No discomfort/risk expected. Some may find stool collection
unpleasant.
- Electrocardiogram: Minor skin irritation may occur at the site of the
electrodes but will be resolved once the electrodes are removed from the skin.
450 East Jamie Court 1
South San Francisco, CA 94080
US
450 East Jamie Court 1
South San Francisco, CA 94080
US
Listed location countries
Age
Inclusion criteria
The study will enroll male and female adult subjects with moderate to severe UC.
Inclusion criteria (subjects must meet the following criteria to be randomized
into the study):
1. Male and female subjects aged 18 to 75 years, inclusive.
2. Diagnosis of UC for at least 3 months prior to screening.
3. Moderate to severe UC, as defined by a total MCS of 6 to 12 inclusive at
baseline, with a MES >= 2 (confirmed by central reader).
4. Eligible for adalimumab (or adalimumab biosimilar) therapy.
5. Naïve to therapy with approved or investigational biologics/tofacitinib
including any anti-tumor necrosis factor (TNF) therapy, vedolizumab, or
ustekinumab.
6. If subjects are receiving the following treatments, they must be on a stable
dose for at least 4 weeks prior to randomization:
a. 5-aminosalicylates (5-ASAs) (not exceeding 4.8 g per day).
b. Oral corticosteroids (not exceeding prednisone 20 mg, budesonide 9 mg, or
equivalent).
c. 6-mercaptopurine (6-MP) (any stable dose).
d. Azathioprine (AZA) (any stable dose).
e. Methotrexate (MTX) (any stable dose).
Note: subjects may be using 5-ASA and only 1 of the other medications listed
(oral corticosteroids/6 MP/AZA/MTX).
7. If subjects are receiving bile-salt sequestrant, they must be on a stable
dose for at least 3 months prior to randomization.
8. If subjects are receiving any nonprohibited medications, they must agree to
maintain stable doses of concomitant medications for UC until the end of the
safety follow-up period.
9. Unlikely to conceive.
10. Women of childbearing potential (WOCBP) must have a negative pregnancy test
at screening and at the randomization visit prior to the first dose of study
drug.
11. Able to participate fully in all aspects of this clinical trial.
12. Written informed consent must be obtained and documented.
Exclusion criteria
1. A diagnosis of Crohn*s disease (CD), indeterminate colitis, or presence or
history of fistula with CD.
2. Disease activity limited to distal 15 cm (proctitis).
3. Current evidence of toxic megacolon, abdominal abscess, symptomatic colonic
stricture, or stoma.
4. History or current evidence of colonic dysplasia or adenomatous colonic
polyps.
5. Current bacterial or parasitic pathogenic enteric infection, including
Clostridium difficile;; known active cytomegalovirus infection; known infection
with hepatitisB or C virus; known infection with human immunodeficiency virus;
infection requiring hospitalization or intravenous (IV) antimicrobial therapy,
or opportunistic infection within 6 months prior to screening; any infection
requiring antimicrobial therapy within 2 weeks prior to screening; history of
more than 1 episode of herpes zoster or any episode of disseminated zoster.
6. A positive diagnostic tuberculosis (TB) test at screening (defined as a
positive QuantiFERON test). In cases where the QuantiFERON test is
indeterminate, the participant may have the test repeated once and if their
second test is negative, they will be eligible. In the event a second test is
also indeterminate, or QuantiFERON is unavailable, the investigator has the
option to perform a purified protein derivative (PPD) skin test. If the PPD
reaction is < 5 mm, then the subject is eligible. If the reaction is >= 5 mm,
or PPD testing is not done, the subject is not eligible. An exception is made
for subjects with a history of latent TB who are currently receiving treatment
for latent TB, will initiate treatment for latent TB before the first dose of
study treatment, or have documentation of completing appropriate treatment for
latent TB within 3 years prior to the first dose of study treatment.
7. Live virus vaccination within 1 month prior to screening.
8. Any prior treatment with an approved or investigational
biologic/tofacitinib, including anti-TNF therapy, vedolizumab, or ustekinumab.
9. Treatment with sirolimus, cyclosporine, mycophenolate, or tacrolimus within
8 weeks prior to randomization.
10. Treatment with IV corticosteroids, rectal corticosteroids, or rectal 5-ASA
within 4 weeks prior to randomization.
11. Fecal microbiota transplantation within 1 month prior to screening.
12. A concurrent clinically significant, serious, unstable, or uncontrolled
underlying cardiovascular, pulmonary, hepatic, renal, gastrointestinal,
genitourinary, hematological, coagulation, immunological, endocrine/metabolic,
or other medical disorder that, in the opinion of the investigator, might
confound the study results, pose additional risk to the subject, or interfere
with the subject*s ability to participate fully in the study.
13. A diagnosis of multiple sclerosis or optic neuritis, or history of a
demyelinating disorder.
14. Known primary or secondary immunodeficiency.
15. History of myocardial infarction, unstable angina, transient ischemic
attack, decompensated heart failure requiring hospitalization, congestive heart
failure (New York Heart Association Class 3 or 4), uncontrolled arrhythmias,
cardiac revascularization, stroke, uncontrolled hypertension, or uncontrolled
diabetes within 6 months of screening.
16. Clinically meaningful laboratory abnormalities at screening that would
affect subject safety, as determined and documented by the investigator.
17. Pregnant or lactating females.
18. Any surgical procedure requiring general anesthesia within 1 month prior to
screening, or planned elective surgery during the study.
19. History of malignant neoplasms or carcinoma in situ within 5 years prior to
screening.
20. Current or recent history of alcohol dependence or illicit drug use that,
in the opinion of the investigator, may interfere with the subject*s ability to
comply with the study procedures.
21. Mental or legal incapacitation or a history of clinically significant
psychiatric disorders at the time of the screening visit that would impact the
ability to participate in the trial according to the investigator.
22. Unable to attend study visits or comply with procedures.
23. Concurrent participation in any other interventional study or received any
investigational therapy within 1 month of randomization.
24. Previous exposure to AMT-101 or recombinant human interleukin-10 (rhIL-10).
25. A known hypersensitivity to AMT-101, adalimumab, or their respective
excipients.
26. Current treatment with antimotility medications or antidiarrheals (except
for bile-salt sequestrants).
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 | EUCTR2020-002833-13-NL |
| CCMO | NL75240.018.20 |