A Study to Investigate the Pharmacokinetics, Pharmacodynamic Effects, Safety and Tolerability of Repeated Dosing of RO5459072 in Volunteers With Celiac Disease

• ClinicalTrials.gov Identifier: NCT02679014
• Recruitment Status: Completed
• First Posted: February 10, 2016
• Last Update Posted: August 25, 2017
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

A randomized, double-blind, placebo-controlled, two treatment, parallel group study to investigate the effects of RO5459072, a cathepsin S inhibitor, on the immune response to a gluten challenge in volunteers with celiac disease. Volunteers with previously diagnosed celiac disease will be randomized to receive either 100 milligrams (mg) RO5459072 or placebo twice daily with food for 28 days (Days 1 to 28).

Condition or disease	Intervention/treatment	Phase
Celiac Disease	Drug: Placebo; Drug: RO5459072	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose, Parallel Study to Investigate the Pharmacokinetics, Pharmacodynamic Effects, Safety and Tolerability of Repeated Dosing of RO5459072 in Volunteers With Celiac Disease
• Actual Study Start Date: March 6, 2016
• Actual Primary Completion Date: August 28, 2016
• Actual Study Completion Date: August 28, 2016

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Participants will receive placebo capsules (2 capsules) twice daily for 28 days.	Drug: Placebo; With the exception of the mornings of Days 7 and 21, placebo capsules will be taken orally with a glass of still water in the morning and evening under fed conditions. On the mornings of Days 7 and 21, placebo will be administered under fasted conditions (overnight fast of at least 8 hours before dosing).
Experimental: RO5459072; Participants will receive RO5459072 100 milligrams (mg) capsules (2*50 mg capsules) twice daily for 28 days.	Drug: RO5459072; With the exception of the mornings of Days 7 and 21, RO5459072 capsules will be taken orally with a glass of still water in the morning and evening under fed conditions. On the mornings of Days 7 and 21, RO5459072 will be administered under fasted conditions (overnight fast of at least 8 hours before dosing).; Other Name: RG7625

Outcome Measures

Primary Outcome Measures :

1. Overall Numbers of Participants who are Responders to the Gluten Challenge, Defined as Participants with an Increase in Number of Gliadin Specific T-cells Above Assay-Specific Thresholds [ Time Frame: Day 13 and Day 29 ]

Secondary Outcome Measures :

1. Percentage of Participants with Adverse Events (AEs) [ Time Frame: Up to Day 35 ]
2. Number of Participants with an Increase in Antibody Titers (Anti-Tissue Transglutaminase [anti-tTG] Immunoglobulin A [IgA] and Immunoglobulin G [IgG] and Anti-Deamidated Gliadin Peptide (anti-DPG) IgA), as Determined Using Enzyme Immunoassay Methods [ Time Frame: Screening, Day 7, Day 13, Day 21, Day 29 and Day 35 (Follow up) ]
3. Lactulose to Mannitol Ratio (LMR), Determined by Urine Concentrations of Lactulose and Mannitol [ Time Frame: Day 7: 1 hour (hr) pre-dose to 1 hr post-dose, 1 hr to 3 hr post-dose, 3 hr to 5 hr post-dose and Day 21: 1 hr pre-dose to 1 hr post-dose, 1 to 3 hr post-dose, 3 hr to 5 hr post-dose ]
4. Change from Baseline in Number of Circulating White Blood Cells [ Time Frame: Day 1 (Baseline), Day 7, Day 13, Day 21, and Day 29 ]
5. Change from Baseline in Concentrations of the 10 kilodalton (kDa) Cluster of Differentiation 74 (CD74) Intermediate (Fragment p10) in B Cells [ Time Frame: Day 1: pre-dose (=Baseline [BL]) and 4 hours (h) post-dose, Day 7: pre-dose and 4 h post-dose, Day 21: pre-dose and 4 h post-dose ]
6. Change from Baseline in Concentrations of Cathepsin S Mass Biomarker [ Time Frame: Day 1 (Baseline), Day 7, Day 13, Day 21 and Day 29 ]
7. Change from Baseline in Concentrations of Cystatin C Biomarker [ Time Frame: Day 1 (Baseline), Day 7, Day 13, Day 21 and Day 29 ]
8. Maximum Response (Emax ) in p10 upon Cathepsin S Inhibition Ex vivo [ Time Frame: Day 1: pre-dose ]
9. Concentration of RO5459072 that Gives Half-maximal Response (EC50) in Ex Vivo p10 Stimulation Assay [ Time Frame: Day 1: pre-dose ]
10. Change from Baseline in 4Beta-hydrocholesterol Concentration [ Time Frame: Day 1 (Baseline), Day 7, Day 13, Day 21 and Day 29 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Volunteers with a biopsy confirmed diagnosis of celiac disease
• Human leukocyte antigen (HLA) serotype DQ 2.5 and HLA-DQ 8 haplotypes
• Maintaining a gluten-free diet for at least one year. Compliance will be assessed by serology, compatible responses to a self-reported assessment of gluten-free diet adherence and the absence of typical celiac disease symptoms
• Able to participate and to comply with the study restrictions including the requirements of the gluten challenge

Exclusion Criteria:

• A diagnosis of non-celiac gluten sensitivity
• A personal history of food intolerance other than to gluten, or diagnosis of galactosemia, lactose, galactose or fructose intolerance
• A personal history of severe acute symptomatic reaction to sporadic gluten ingestion
• A diagnosis of refractory celiac disease or presence of severe complications of celiac disease
• Diagnosed or suspected immunoglobulin A (IgA) deficiency
• Acute inflammatory bowel disease (ulcerative colitis, Crohn's disease), gastrointestinal obstruction or sub-occlusive syndromes, digestive perforation or risk of digestive perforation, painful abdominal syndromes of undetermined cause
• A history of stomach or intestinal surgery or resection. Appendectomy and hernia repair are acceptable
• Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple allergies (non-active hay fever is acceptable)
• Immunocompromised or with reduced immune function considered to be clinically significant by the Investigator
• Immunization within 30 days before the screening visit or planning vaccination during the study
• Women who are pregnant or lactating, or who are of child-bearing potential and do not agree to comply with requirements for contraceptive use. Men who do not agree to comply with requirements for contraceptive use and restrictions on sperm donation
• Participation in an investigational drug or device study within the three months preceding the screening visit

Contacts and Locations

Locations

United Kingdom

Hammersmith Medicines Research Ltd.

London, United Kingdom, NW10 7EW

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02679014
• Other Study ID Numbers: BP29911; 2015-002864-18 ( EudraCT Number )
• First Posted: February 10, 2016
• Last Update Posted: August 25, 2017
• Last Verified: August 2017

Additional relevant MeSH terms:

Celiac Disease; Malabsorption Syndromes; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Metabolic Diseases; Petesicatib; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action