Clinical trial NCT06310291: VTP-1000 in Adults with Celiac Disease
Official title: A Phase 1, First in Human, Randomized, Placebo-controlled Trial with a Controlled Gluten Challenge to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of VTP-1000 in Adults with Celiac Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Celiac Disease
Lead sponsor: Barinthus Biotherapeutics
Sponsor class: INDUSTRY
First posted: 2024-03-15
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The Single Ascending Dose part of the trial contains a placebo controlled randomized 4+2 design, where four participants will receive active IMP and two placebo. The Multiple Ascending Dose is a standard sequential design
Primary purpose: TREATMENT

Brief summary: GLU001 is a first-in-human clinical trial to assess the safety and tolerability of VTP-1000 for adults with celiac disease. This trial will assess VTP-1000 at various dose levels compared to placebo in a single ascending dose (SAD) and multiple ascending dose (MAD) format. Participants will be followed for a short period of time to assess the impact of VTP-1000 on their immune system (Adverse events, reactions in the blood, and physical exam differences). Participants enrolled in the MAD portion of the trial will undergo a gluten challenge to assess the impact exposure to gluten has on participants after administration of VTP-1000.

Detailed description: VTP-1000 is a gluten-derived (GLU) peptide immunotherapy that is designed to induce antigen-specific immune tolerance against gluten in patients with celiac disease. The technology underlying VTP-1000 consists of the sponsor's proprietary self-assembling nanoparticles based on amphiphilic peptides tolerance immunotherapy (SNAP-TI) platform which has been configured to package 12 GLU peptide antigens and rapamycin into nanoparticles of \~20 nm diameter.

The goal of treatment with VTP-1000 is to induce tolerance to gluten in patients with coeliac disease by activating antigen-specific regulatory T (Treg) cells that promote tolerance and reducing pre-existing, pathogenic antigen-specific effector T (Teff) cells that underly disease pathogenesis. In turn, this may allow for better management of the condition.

GLU001 is a multi-center phase I first in human study to assess the safety and tolerability of VTP-1000 in adults with celiac disease. The trial also aims to demonstrate proof-of-principle of induction of immune tolerance and early proof-of-concept for VTP-1000 as a potential treatment for coeliac disease based on assessment of pharmacodynamics and preliminary efficacy determined by means of a controlled gluten challenge.

GLU001 will be conducted as a randomized double-blind placebo-controlled study in two parts - Part A and Part B. Part A will be a single ascending dose (SAD) followed by Part B a multiple ascending dose (MAD) which incorporates a gluten challenge.

Part A (Single Ascending Dose)

A stepwise single dose escalation of 3 dose levels of VTP-1000 is planned. A total of 6 participants will be treated at each dose level (4 will receive VTP-1000 and 2 will receive matched placebo). A sentinel dosing approach will be followed, with the first 2 participants randomized to receive VTP1000 or placebo in a 1:1 ratio. Subsequent participants will be randomized in a 3:1 ratio at least 7 days after the second sentinel participant has received trial intervention. Participants will be screened for eligibility up to 28 days prior treatment. Participants will be followed for 21 days after dosing including a 3-day domicile period following administration of VTP-1000.

Part B (Multiple Ascending Dose)

A stepwise multiple dose escalation of up to 3 dose levels of VTP-1000 is planned. A total of 8 participants will be treated at each dose level (6 will receive VTP-1000 and 2 will receive matched placebo). A sentinel dosing approach will be followed, with the first 2 participants randomized to receive VTP1000 or placebo in a 1:1 ratio. Subsequent participants will be randomized in a 3:1 ratio at least 7 days after the second sentinel participant has received trial intervention. Participants will be screened for eligibility up to 28 days prior to the start of treatment. Eligible participants will receive 3 doses of trial intervention every 2 weeks at a given dose level with and followed for 57 days. After completion of the third dose of trial intervention, participants will undergo a gluten challenge.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of celiac disease as confirmed by positive serology and intestinal histology
* Presence of Human Leukocyte Antigen (HLA)-DQ2.5 genotype
* Participants who are on a well controlled gluten restricted diet
* Negative or weak positive anti-tissue transglutaminase (tTG) IgA antibodies and negative or weak positive anti-deamidated gliadin peptide IgG (anti-DGP)-IgA/IgA antibodies
* Non-pregnant or breast feeding females
* No other clinical significant findings at screening

Exclusion Criteria:

* Refractory celiac disease
* Selective IgA deficiency
* Positive for HLA-DQ8
* Known wheat allergy or that is Type I hypersensitivity
* Active inflammatory bowel disease or other condition with symptoms that will be similar to celiac disease

Primary outcomes:
measure: Treatment Emergent Adverse Events, Serious Adverse Events and Adverse Events of Special Interest (AESIs)
timeFrame: Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
measure: Changes from baseline and clinically significant abnormalities in standard Clinical Chemistry laboratory safety parameters
timeFrame: Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
measure: Changes from baseline and clinically significant abnormalities in standard Coagulation laboratory safety parameters
timeFrame: Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
measure: Changes from baseline and clinically significant abnormalities in standard hematology laboratory safety parameters
timeFrame: Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
measure: Changes from baseline and clinically significant abnormalities in standard urinalysis laboratory safety parameters
timeFrame: Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
measure: Changes from baseline and clinically significant abnormalities 12-lead electrocardiogram (ECG) parameters
timeFrame: Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
measure: Changes from baseline and clinically significant abnormalities in vital signs
timeFrame: Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
measure: Number of participants with changes from baseline in anti-tissue transglutaminase (anti-tTG) immunoglobulin A (IgA) antibodies
timeFrame: Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
measure: Changes in physical examination findings
timeFrame: Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
Secondary outcomes:
measure: PART A SAD:Maximum concentration in plasma (Cmax) rapamycin component
timeFrame: SAD Day 1 pre-dose; 0.083 hours* (±2 minutes), 0.25 hours* (±5 minutes), 0.5 hours (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±10 minutes), 24 hours (±30 minutes), 48 hours (±2 hours), 120 hours (±3 hours).
measure: PART A SAD: Time corresponding to Cmax (Tmax) of rapamycin component
timeFrame: Day 1 pre-dose; 0.083 hours* (±2 minutes), 0.25 hours* (±5 minutes), 0.5 hours (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±10 minutes), 24 hours (±30 minutes), 48 hours (±2 hours), 120 hours (±3 hours).
measure: AUC from time 0 to last quantifiable concentration (AUC0-t) of rapamycin component
timeFrame: Day 1 pre-dose; 0.083 hours* (±2 minutes), 0.25 hours* (±5 minutes), 0.5 hours (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±10 minutes), 24 hours (±30 minutes), 48 hours (±2 hours), 120 hours (±3 hours).
measure: AUC extrapolated to infinity (AUC0-∞)of rapamycin component
timeFrame: Day 1 pre-dose; 0.083 hours* (±2 minutes), 0.25 hours* (±5 minutes), 0.5 hours (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±10 minutes), 24 hours (±30 minutes), 48 hours (±2 hours), 120 hours (±3 hours).
measure: Half-life of rapamycin component
timeFrame: Day 1 pre-dose; 0.083 hours* (±2 minutes), 0.25 hours* (±5 minutes), 0.5 hours (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±10 minutes), 24 hours (±30 minutes), 48 hours (±2 hours), 120 hours (±3 hours).
measure: Clearance of rapamycin component
timeFrame: Day 1 pre-dose; 0.083 hours* (±2 minutes), 0.25 hours* (±5 minutes), 0.5 hours (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±10 minutes), 24 hours (±30 minutes), 48 hours (±2 hours), 120 hours (±3 hours).
measure: Volume of distribution of rapamycin component
timeFrame: Day 1 pre-dose; 0.083 hours* (±2 minutes), 0.25 hours* (±5 minutes), 0.5 hours (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±10 minutes), 24 hours (±30 minutes), 48 hours (±2 hours), 120 hours (±3 hours).
measure: Part B MAD:Maximum concentration in plasma (Cmax) rapamycin component
timeFrame: Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
measure: Part B MAD:Time corresponding to Cmax (Tmax) of rapamycin component
timeFrame: Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
measure: Part B MAD:AUC from time 0 to last quantifiable concentration (AUC0-t) of rapamycin component
timeFrame: Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
measure: Part B MAD:AUC extrapolated to infinity (AUC0-∞)of rapamycin component
timeFrame: Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
measure: Part B MAD: Half-life of rapamycin component
timeFrame: Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
measure: Part B MAD: Clearance of rapamycin component
timeFrame: Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
Other outcomes:
measure: Gluten Antigen-specific T Cell Responses - Enzyme linked immunospot (ELISpot)
timeFrame: Part A (SAD): Day 1 pre-dose, Days 8 and 15 Part B (MAD): Day 1 pre-dose, Days 8, 22 and 36, Day 43 pre-challenge, Days 50 and 57
measure: Gluten Antigen-specific T Cell Responses - Intracellular cytokine staining (ICS)
timeFrame: Part A (SAD): Day 1 pre-dose, Days 8 and 15 Part B (MAD): Day 1 pre-dose, Days 8, 22 and 36, Day 43 pre-challenge, Days 50 and 57
measure: T cell receptor (TCR) sequencing
timeFrame: Part A (SAD): Day 1 pre-dose, Day 15 Part B (MAD): Day 1 pre-dose, Day 43 pre-challenge and Day 57
measure: Serum Cytokine Concentrations
timeFrame: SAD Day 1 pre-dose, 4 hours and 24 hours postdose MAD: Days 1, 15 and 29 pre-dose and 4 hours post-dose
measure: Cytokine Whole Blood Stimulation
timeFrame: Part A (SAD): Day 1 pre-dose, Days 8 and 15 Part B (MAD): Day 1 pre-dose, Days 8, 22 and 36, Day 43 pre-challenge and Days 50 and 57
Locations:
city: Los Angeles
country: United States
facility: Parexel EPCU LA
state: California
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: St. Petersburg
country: United States
facility: GCP Research
state: Florida
city: Baltimore
country: United States
facility: Parexel EPCU Baltimore
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Raleigh
country: United States
facility: North Carolina Clinical Research
state: North Carolina
city: Columbus
country: United States
facility: Centricity Research
state: Ohio
city: Austin
country: United States
facility: PPD Research Unit
state: Texas
Study officials:
References: