Clinical trial NCT02679014: A Study to Investigate the Pharmacokinetics, Pharmacodynamic Effects, Safety and Tolerability of Repeated Dosing of RO5459072 in Volunteers With Celiac Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Celiac Disease
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-02-10
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility 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

Primary outcomes:
measure: 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
timeFrame: Day 13 and Day 29
Secondary outcomes:
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: Up to Day 35
measure: 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
timeFrame: Screening, Day 7, Day 13, Day 21, Day 29 and Day 35 (Follow up)
measure: Lactulose to Mannitol Ratio (LMR), Determined by Urine Concentrations of Lactulose and Mannitol
timeFrame: 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
measure: Change from Baseline in Number of Circulating White Blood Cells
timeFrame: Day 1 (Baseline), Day 7, Day 13, Day 21, and Day 29
measure: Change from Baseline in Concentrations of the 10 kilodalton (kDa) Cluster of Differentiation 74 (CD74) Intermediate (Fragment p10) in B Cells
timeFrame: 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
measure: Change from Baseline in Concentrations of Cathepsin S Mass Biomarker
timeFrame: Day 1 (Baseline), Day 7, Day 13, Day 21 and Day 29
measure: Change from Baseline in Concentrations of Cystatin C Biomarker
timeFrame: Day 1 (Baseline), Day 7, Day 13, Day 21 and Day 29
measure: Maximum Response (Emax ) in p10 upon Cathepsin S Inhibition Ex vivo
timeFrame: Day 1: pre-dose
measure: Concentration of RO5459072 that Gives Half-maximal Response (EC50) in Ex Vivo p10 Stimulation Assay
timeFrame: Day 1: pre-dose
measure: Change from Baseline in 4Beta-hydrocholesterol Concentration
timeFrame: Day 1 (Baseline), Day 7, Day 13, Day 21 and Day 29
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Hammersmith Medicines Research Ltd.
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: