* To evaluate the effect of EDP1815 on the systemic immune system.* To evaluate the safety and tolerability of EDP1815 in multiple formulations.
ID
Source
Brief title
Condition
- Immune disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* KLH challenge
o DTH after intradermal KLH re-challenge. Response characterization by Laser
Speckle Contrast Imaging (LSCI) and erythema by multispectral imaging
o Serology: anti-KLH IgM and IgG
o Ex vivo lymphocyte activation upon KLH re-challenge. Response
characterization by ELISPOT.
o Suction blister exudates: cytokines TNF*, IL8, IFN-*, IL6, IL-1*, IL-10,
IL-33, TSLP, and immunophenotyping from cohort 2 onwards
* Whole blood ex-vivo Phytohaemagglutinin (PHA) and Lipopolysaccharide (LPS)
challenges with cytokine release (LPS: TNF*, IL-6, IL-1b, IL-8, IL-2, IFN-*
and IL-10. PHA: IL-2 en IFN-*) as read-out measured by MSD.
* (Changes in) regulatory T cells and B cell subsets
* Blood chemokine and cytokine levels
Secondary outcome
* Serious adverse event (SAE) and adverse event (AE) incidents
* Clinical safety laboratory measurements
* Electrocardiogram (ECG) measurements
* Vital sign measurements
* Chemistry and hematology panels
* Physical examination
* Bristol Stool Scale and stool questionnaire
* Persistent EDP1815 prevalence in stool samples
o Strain-specific PCR
* Gut microbiota composition in stool samples
o 16S RNA sequencing
* Specific markers of gastrointestinal (GI) integrity
o Faecal calprotectin (only cohort 1)
* Immune biomarkers
o Cytokines e.g. TNF-* and IL-6
o Immunoglobulins e.g. IgG (including individual subclasses IgG1 to IgG4), IgM,
IgA
* Leukocyte subsets e.g. CD3+, CD4+, CD8+, CD19+, NK-cells and CD14+
Background summary
Over the past decades evidence has emerged for an interplay between the gut
microbial flora (microbiome) and the (systemic) immune system. Alteration in
the composition of the gut microbiome has been associated with the presence of
several (auto)inflammatory diseases. Evelo Biosciences has identified and
selected individual microbial strains of human commensal bacteria based on
their properties to modulate the systemic immune system to use as therapeutics
for auto-immune diseases e.g. psoriasis and rheumatoid arthritis. These
individual microbial strains are called monoclonal microbials. Since these
monoclonal microbials are human commensal organisms they are likely to be
well-tolerated and in addition are restricted to the gut when orally
administered. If they are capable of modulating multiple immune pathways in
humans, as different preclinical studies are suggesting, they have the
potential to become an attractive therapeutic strategy in patients with (auto)
inflammatory diseases, either as monotherapy or in combination with other
agents.
Study objective
* To evaluate the effect of EDP1815 on the systemic immune system.
* To evaluate the safety and tolerability of EDP1815 in multiple formulations.
Study design
This is a single centre, double-blind, randomized, placebo-controlled trial to
evaluate the effect of EDP1815 on the systemic immune system, using a KLH
challenge. A flowchart of the study is displayed in Figure 1 below. The EDP1815
dose level to be tested is 8.0 x 10'11' total cells in each cohort (i.e.
approximately 5x of the allometric scaled preclinical efficacious dose level).
Participants who pass screening will be randomised either to the active
(EDP1815) or placebo group. Each cohort will consist of 16 subjects, of whom 12
will receive EDP1815 and 4 will receive matching placebo. Dosing will be
initiated on Day 1 and continue for 28 days, the KLH challenge will be the key
pharmacodynamic endpoint.
Intervention
EPD1815
Study burden and risks
EDP1815 is a pharmaceutical preparation of a single strain of Prevotella
histicola. Prevotella histicola is a commensal organism found in all human
populations studied to date. EDP1815 drug-substance has viability of <0.02% and
is not genetically modified.
In clinical study EDP1815-101, a total of 104 subjects including healthy
volunteers and subjects with mild to moderate psoriasis and atopic dermatitis
participated in Cohorts 1 * 6. Subjects were randomized to EDP1815 or placebo
in a 2:1 ratio with a total of 70 subjects receiving EDP1815 in this study: 2
subjects received a single dose; 16 subjects received multiple daily doses for
14 days (healthy volunteers); 36 subjects received multiple daily doses for 28
days (psoriasis), and 16 subjects received multiple daily doses for 28 days
(atopic dermatitis). Throughout this study the safety profile of EDP1815 was
comparable to placebo. There have been no serious adverse events, no SUSARs,
and no adverse events of severe intensity. No subjects required cessation of
dosing due to an AE. Additionally, there has been no evidence of systemic
absorption in the patients studied and no clinically relevant results nor
trends in laboratory results.
While Prevotella is a human commensal, it is a potentially pathogenic
micro-organism. Most frequently reported are urinary tract infections with a
relatively mild clinical course, in most cases in immuno-compromised patients,
who are not part of the current protocol. P. histicola and EDP1815 specifically
has been tested and has been found to be sensitive for various antibiotics
which will be administered in the current protocol if considered necessary.
The study design has been used previously in many studies, and is accepted by
scientists and regulatory authorities. The first three study drug
administrations per cohort will be done in the clinic under medical
supervision. The subjects receiving any study drug will remain in the clinic
for at least 48 hours after their first study drug administration. Thus, the
subjects can be closely monitored for any adverse signs during the different
treatments. Therefore, providing the protocol is adhered to, careful
observation and medical management will minimize any associated risk in this
study.
For a structured risk assessment see Section 11 of the protocol.
Memorial Drive 620
Cambridge 02139 MA
US
Memorial Drive 620
Cambridge 02139 MA
US
Listed location countries
Age
Inclusion criteria
Participants are eligible to be included in the study only if all of the
following criteria apply:
1. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in
this protocol. Obtained prior to any screening procedures and in accordance
with national, local, institutional guidelines.
2. Age * 18 years to 60 years, inclusive.
3. Participant has a body mass index of * 18 kg/m2 to * 35 kg/m2 at Screening.
4. Contraception:
a. Male participants:
* A male participant must agree to use contraception during their participation
in this study and for a period of 90 days after the last dose and refrain from
donating sperm during this period.
b. Female participants:
* A female participant is eligible to participate if she is not pregnant, does
not plan to become pregnant, not breastfeeding, and at least 1 of the following
conditions applies:
i. Not a woman of child-bearing potential (WOCBP)
OR
ii. A WOCBP who agrees to follow the contraceptive guidance during their
participation in this study and for at least 3 complete menstrual cycles (*90
days) after last EDP1815 dose.
5. CRP * 10 mg/L and faecal calprotectin * 150 mcg/g faeces. Exceedings of
these thresholds may be allowed by the investigator if deemed clinically
irrelevant.
6. The participant has clinical laboratory evaluations (including clinical
chemistry, haematology, and complete urinalysis) within the reference range for
the testing laboratory, unless the results are deemed not to be clinically
significant by the investigator (1 repeat test is permitted).
7. Fitzpatrick skin type I-III (Caucasian).
8. Participants who are overtly healthy as determined by medical evaluation
including medical history, physical examination, laboratory tests, and cardiac
monitoring at Screening and on Day 1.
9. Subject needs to have sufficient space in a refrigerator to store the IMP
during the ambulant dosing phase.
10. Participant has the ability to communicate well with the Investigator in
the Dutch language and willing to comply with the study restrictions.
Only subjects with a negative SARS-CoV-2 qPCR analysis prior to first dosing
will be included in the study
Exclusion criteria
1. Participant has received live attenuated vaccination within 42 days prior to
Screening or intends to have vaccinations during the course of the study.
2. Participant has received any investigational drug or experimental procedure
within 90 days or 5 half-lives, whichever is longer, prior to study
intervention administration or participant was enrolled in an investigational
drug or device study within 90 days prior to first EDP1815 dosing.
3. Participant requires treatment with an anti-inflammatory drug or
prophylactic antibiotics for any reason during the study period. Paracetamol
will be permitted for use as an antipyretic and/or analgesic (maximum of 4
grams/day in any 24-hour period).
4. Participant has an active infection (e.g. sepsis, pneumonia, abscess) or
recurrent infection, or has had an infection requiring antibiotic treatment
within 42 days prior to Investigational Medicinal Product (IMP) administration.
5. Participant is diagnosed with tuberculosis (TB, as per positive skin test
(Mantoux) or IFN-* release assay), or history of TB, or latent TB, or recent
contact with TB (patient); having travelled to countries where TB is endemic
within 56 days of planned drug administration or planning to travel to
countries where TB is endemic from the moment of drug administration until 90
days after the end of the study.
6. Participant has renal or liver impairment, defined as:
a. For women, serum creatinine level * 125 *mol/L; for men, * 135 *mol/L
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) * 1.5 x
upper limit of normal (ULN), or
c. Alkaline phosphatase (ALP) and/or bilirubin > 1.5 x ULN
Exceedings of these thresholds may be allowed by the investigator
if deemed clinically
irrelevant.
7. Participant has active neoplastic disease or history of neoplastic disease
within 5 years of Screening (except for basal or squamous cell carcinoma of the
skin or carcinoma in situ that has been definitively treated with standard of
care).
8. Impaired cardiac function or clinically significant cardiac diseases,
including any of the following:
a. Unstable angina or acute myocardial infarction * 90 days prior to Screening;
b. Clinically significant heart disease (e.g. symptomatic congestive heart
failure [e.g. >New York Heart Association [NYHA] Class 2]; uncontrolled
arrhythmia, or hypertension; history of labile hypertension or poor compliance
with an antihypertensive regimen.
9. Participant with a positive screening result for hepatitis B surface
antigen, anti-hepatitis B core, hepatitis C, or HIV.
10. Participants with gastrointestinal tract disease (e.g. short bowel
syndrome, diarrhoea predominant irritable bowel syndrome [IBS], celiac disease)
that could interfere with the subject*s safety or pharmacodynamic effect of the
monoclonal microbial.
11. Serious psychiatric or medical conditions that, in the opinion of the
investigator, could interfere with treatment, compliance, or the ability to
give consent.
12. The participant has a history of hypersensitivity or allergies to
Prevotella (or Prevotella containing probiotics) including any associated
excipients, or has a history of hypersensitivity or allergies to placebo
capsule/powder (magnesium stearate, microcrystalline cellulose, colloidal
silicon dioxide, hydroxypropylmethylcellulose, or mannitol) or to the hard
capsule shells (hydroxyl propyl methyl cellulose and titanium dioxide), or has
a known allergy against Alhydrogel®.
13. Participant has a history of Schistosomiasis (infection with Schistosoma
parasite).
14. The participant has taken any over-the-counter (OTC) medication (with the
exception of paracetamol and anti-histamines) within 14 days prior to Baseline
(Day -1) or any prescription medications or nutraceuticals (e.g. supplements
including high doses of probiotics and prebiotics, as usually found in
capsules/tablets/powders) within 28 days prior to Baseline (Day -1) or
anticipates an inability to abstain from these products for the duration of the
study period. Note that probiotic and prebiotic foods e.g. yoghurts that
contain low doses are allowed.
15. The participant uses probiotic capsules within 14 days prior to screening.
16. The participant has a significant history of drug abuse or regular use of
illicit drugs or a history of alcohol abuse within 1 year prior to Screening.
17. The participant uses more than 10 cigarettes per day and/or is unable to
refrain from cigarettes or tobacco use or other nicotine-containing products
(e.g., patches) during 4 consecutive days.
18. The participant has donated more than 400 mL of blood or blood products
within 90 days prior to Baseline (Day -1) or plans to donate blood during the
study.
19. The participant has a diastolic blood pressure *50 or *90 mm Hg, or a
systolic blood pressure *105 or *140 mm Hg at Screening or Baseline (Day -1)
unless deemed to be not clinically significant by the investigator.
20. The participant has had an acute, clinically significant illness or major
surgery within 30 days prior to screening.
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-002658-65-NL |
| CCMO | NL67464.056.18 |
| Other | NL8676 |
| OMON | NL-OMON20845 |