VTP-1000 in Adults With Celiac Disease

Celiac Disease Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06310291
• Other study ID #: GLU001
• Status: Not yet recruiting
• Phase: Early Phase 1
• Start date: April 2024
• Est. completion date: August 2025

Study information

• Verified date: March 2024
• Source: Barinthus Biotherapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

VTP-1000 is a gluten-derived (GLU) peptide immunotherapy that is designed to induce antigen-specific immune tolerance against gluten in patients with coeliac 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 antigenspecific effector T (Teff) cells that underly disease pathogenesis. In turn, this may allow for better management of the condition.

This is the first clinical trial with VTP-1000, therefore the primary endpoint will be assessment of the safety and tolerability of single and multiple dosing and determination of a dose and schedule for further investigation. 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.

Trial Design

This is a Phase I, First in Human, multicentre trial conducted in 2 parts; a randomised double-blind placebo controlled SAD part (Part A) followed by a randomised double-blind placebo-controlled MAD part (Part B) incorporating a gluten challenge component.

Part A (Single Ascending Dose)

A stepwise single dose escalation of 3 dose levels of VTP-1000 is planned. Participants will be screened for eligibility in the period 28 days to 2 days prior to the start of treatment. Eligible participants will be admitted to the clinic on the day before dosing (Day -1). Eligibility will be reconfirmed prior to a single dose of VTP-1000 administered by intramuscular injection on Day 1, followed by inpatient observation and assessment for a 48hour period prior to discharge from the clinic on Day 3. Participants will be followed for 21 days after dosing, with follow-up visits on Days 3, 5, 8 and 15 and an End of Trial (EOT) visit on Day 22.

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 randomised to receive VTP1000 or placebo in a 1:1 ratio. Subsequent participants will be randomised in a 3:1 ratio at least 7 days after the second sentinel participant has received trial intervention. The medical monitor will review the safety and tolerability data to confirm the safety profile is acceptable for the first 2 participants in a dose level before the next participant receives trial intervention. Subsequent participants can be dosed in parallel to the third.

Part B (Multiple Ascending Dose)

A stepwise multiple dose escalation of up to 3 dose levels of VTP-1000 is planned, commencing at the starting dose (and frequency) determined by the Safety Monitoring Committee (SMC) review following completion of Part A (SAD). Participants will be screened for eligibility in the period 28 days to 1 day prior to the start of treatment. Eligible participants will receive 3 doses of trial intervention every 2 weeks (on Days 1, 15 and 29) at a given dose level with follow-up on Days 8, 22 and 36. Telephone calls to the participant will also be made by the trial site staff on the day after each treatment day (Days 2, 16 and 30). Two weeks after completion of the third dose of trial intervention, participants will undergo a gluten challenge on Day 43, with a follow-up assessment on Day 50. An EOT visit will be performed on Day 57.

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 randomised to receive VTP1000 or placebo in a 1:1 ratio. Subsequent participants will be randomised in a 5:1 ratio at least 7 days after the second sentinel participant has received all 3 doses of trial intervention, following review of safety and tolerability data from the first 2 participants by the medical monitor to confirm the safety profile is acceptable.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 45
• Est. completion date: August 2025
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Celiac Disease

Intervention

Biological:
• VTP-1000
Intramuscular (IM) injection comprised of self-assembling nanoparticles of gluten peptides and a rapamycin component

Other:
• Matched Placebo
Intramuscular (IM) injection comprised of saline solution

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Barinthus Biotherapeutics

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Gluten Antigen-specific T Cell Responses - Enzyme linked immunospot (ELISpot)	Peripheral Blood Mononucleocytes (PBMCs) will be isolated at the trial site or at a Central Laboratory. Following PBMC isolation, analysis of the magnitude of gluten antigen-specific T cell responses (Treg and Teff) in peripheral blood will be performed by the sponsor using enzyme linked immunospot (ELISpot)	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
Other	Gluten Antigen-specific T Cell Responses - Intracellular cytokine staining (ICS)	Peripheral Blood Mononucleocytes (PBMCs) will be isolated at the trial site or at a Central Laboratory. Following PBMC isolation, analysis of the magnitude of gluten antigen-specific T cell responses (Treg and Teff) in peripheral blood will be performed by the sponsor using intracellular cytokine staining (ICS) as specified in the respective Analytical Protocol.	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
Other	T cell receptor (TCR) sequencing	Whole Blood sampling with sequencing The whole blood will be isolated, frozen and stored at -80°C until shipped for analysis. Full details on blood sample collection, processing and handling requirements will be provided in the Laboratory Manual	Part A (SAD): Day 1 pre-dose, Day 15 Part B (MAD): Day 1 pre-dose, Day 43 pre-challenge and Day 57
Other	Serum Cytokine Concentrations	2 mL whole blood samples will be drawn for evaluation of Interleukin 2 (IL-2) in serum.Samples will be stored at -80°C until shipped to a Central Laboratory for analysis. Full details on blood sample collection, processing and handling requirements will be provided in the Laboratory Manual.; Analysis of IL-2 concentration (and optionally additional cytokines) will be performed at the Central Laboratory using a multiplex cytokine (Meso Scale Discovery S-plex) method as specified in the respective Analytical Protocol.	SAD Day 1 pre-dose, 4 hours and 24 hours postdose MAD: Days 1, 15 and 29 pre-dose and 4 hours post-dose
Other	Cytokine Whole Blood Stimulation	Five 4 mL samples will be drawn and transferred to Greiner Item Number 454088 Vacuette® tubes containing stimulation cocktails for evaluation of cytokines in whole blood stimulated with GLU peptide antigens.Samples will be incubated for 24 hours before processing to sera and stored at -80°C until shipped for analysis. Full details on blood sample collection, processing and handling requirements will be provided in the Laboratory Manual.; Analysis of sera will be performed at a Central Laboratory using a single or multiplex cytokine method as specified in the respective Analytical Protocol.	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
Primary	Treatment Emergent Adverse Events, Serious Adverse Events and Adverse Events of Special Interest (AESIs)	Incidence and severity of treatment-emergent adverse events (TEAEs) , Serious Adverse Events (SAEs) , Adverse Events of Special Interest (AESIs) and adverse events leading to trial intervention discontinuation or trial withdrawal according to NCI CTCAE Version 5.0	Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
Primary	Changes from baseline and clinically significant abnormalities in standard Clinical Chemistry laboratory safety parameters	Changes from baseline and clinically significant abnormalities in standard clinical laboratory safety parameters according to NCI CTCAE Version 5.0	Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
Primary	Changes from baseline and clinically significant abnormalities in standard Coagulation laboratory safety parameters	Measurement of in standard clinical laboratory safety parameters according to NCI CTCAE Version 5.0	Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
Primary	Changes from baseline and clinically significant abnormalities in standard hematology laboratory safety parameters	Measurement of standard hematology clinical laboratory safety parameters according to NCI CTCAE Version 5.0	Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
Primary	Changes from baseline and clinically significant abnormalities in standard urinalysis laboratory safety parameters	Measurement of standard urinalysis clinical laboratory safety parameters according to NCI CTCAE Version 5.0	Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
Primary	Changes from baseline and clinically significant abnormalities 12-lead electrocardiogram (ECG) parameters	Changes from baseline and clinically significant abnormalities in 12-lead ECG parameters recorded according to NCI CTCAE Version 5.0	Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
Primary	Changes from baseline and clinically significant abnormalities in vital signs	Changes from baseline and clinically significant abnormalities in vital signs according to NCI CTCAE Version 5.0	Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
Primary	Number of participants with changes from baseline in anti-tissue transglutaminase (anti-tTG) immunoglobulin A (IgA) antibodies	Measurement of anti tTG immunoglobulin at screening and post treatment	Participants will be assessed for up to 21 days and 57 days post first dose for SAD and MAD parts of the study respectively.
Primary	Changes in physical examination findings	Full physical examination required at screening; symptom-directed physical examination at all other clinic visits. Each physical examination must include a review of the administration sites.	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	PART A SAD:Maximum concentration in plasma (Cmax) rapamycin component	Blood concentration of the rapamycin component of VTP1000 at specified timepoints measured using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and standard pharmacokinetic parameters	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).
Secondary	PART A SAD: Time corresponding to Cmax (Tmax) of rapamycin component	Blood concentration of the rapamycin component of VTP1000 at specified timepoints measured using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and standard pharmacokinetic parameters	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).
Secondary	AUC from time 0 to last quantifiable concentration (AUC0-t) of rapamycin component	Blood concentration of the rapamycin component of VTP1000 at specified timepoints measured using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and standard pharmacokinetic parameters	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).
Secondary	AUC extrapolated to infinity (AUC0-8)of rapamycin component	Blood concentration of the rapamycin component of VTP1000 at specified timepoints measured using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and standard pharmacokinetic parameters	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).
Secondary	Half-life of rapamycin component	Blood concentration of the rapamycin component of VTP1000 at specified timepoints measured using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and standard pharmacokinetic parameters	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).
Secondary	Clearance of rapamycin component	Blood concentration of the rapamycin component of VTP1000 at specified timepoints measured using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and standard pharmacokinetic parameters	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).
Secondary	Volume of distribution of rapamycin component	Blood concentration of the rapamycin component of VTP1000 at specified timepoints measured using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and standard pharmacokinetic parameters	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).
Secondary	Part B MAD:Maximum concentration in plasma (Cmax) rapamycin component	The Maximum concentration in plasma (Cmax) results will be reviewed from Part A (SAD) and the Part B (MAD) schedule may be updated accordingly to include additional sampling timepoints and inclusion of the derivation of pharmacokinetic parameters, as applicable.	Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
Secondary	Part B MAD:Time corresponding to Cmax (Tmax) of rapamycin component	The Cmax(Tmax) results will be reviewed from Part A (SAD) and the Part B (MAD) schedule may be updated accordingly to include additional sampling timepoints and inclusion of the derivation of pharmacokinetic parameters, as applicable.	Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
Secondary	Part B MAD:AUC from time 0 to last quantifiable concentration (AUC0-t) of rapamycin component	The AUC from time 0 to last quantifiable concentration (AUC0-t) results will be reviewed from Part A (SAD) and the Part B (MAD) schedule may be updated accordingly to include additional sampling timepoints and inclusion of the derivation of pharmacokinetic parameters, as applicable.	Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
Secondary	Part B MAD:AUC extrapolated to infinity (AUC0-8)of rapamycin component	The pharmacokinetic results will be reviewed from Part A (SAD) and the Part B (MAD) schedule may be updated accordingly to include additional sampling timepoints and inclusion of the derivation of pharmacokinetic parameters, as applicable.	Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
Secondary	Part B MAD: Half-life of rapamycin component	The Half-life results will be reviewed from Part A (SAD) and the Part B (MAD) schedule may be updated accordingly to include additional sampling timepoints and inclusion of the derivation of pharmacokinetic parameters, as applicable.	Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50
Secondary	Part B MAD: Clearance of rapamycin component	The clearance of rapamycin component results will be reviewed from Part A (SAD) and the Part B (MAD) schedule may be updated accordingly to include additional sampling timepoints and inclusion of the derivation of pharmacokinetic parameters, as applicable.	Part B (MAD): Days 1, 15 and 29 pre-dose and 4 hours (±10 minutes) post-dose; Day 43 pre-challenge and Day 50