Impaired Glucose Tolerance, Psoriasis, Psoriatic Arthritis, Type 2 Diabetes
Conditions
Keywords
liraglutide, GLP-1 receptor agonists
Brief summary
Exploratory, double-blind randomized, placebo-controlled, Phase II study to evaluate the effect(s) of short-term administration of liraglutide, a GLP-1R (glucagon-like peptide-1 receptor) agonist on joint and skin inflammation in patients with active Psoriatic Arthritis.
Detailed description
The primary purpose of this study is to determine whether short-term (12-week) administration of the GLP-1R agonist, liraglutide, will improve joint and skin swelling in patients with active Psoriatic Arthritis compared to placebo. Background: Psoriatic Arthritis is a systemic inflammatory T-cell disorder affecting the joints and spine, and is associated with an elevated risk for Type 2 Diabetes and Cardiovascular Disease. In addition to classical effects on glycemic-lowering, GLP-1R agonists are anti-diabetes agents which also have anti-inflammatory properties that may be clinically useful for patients with inflammatory diseases, particularly those with co-morbid metabolic disease. While a few small exploratory studies in patients with psoriasis have demonstrated that GLP-1R agonists reduce the severity of skin plaques, dedicated prospective, randomized mechanistic studies evaluating potential mechanisms by which GLP-1R agonists exert anti-inflammatory action(s) in humans with inflammatory disease is lacking. Objectives: Primary objective is to evaluate the clinical efficacy of short-term liraglutide (GLP-1R agonist) administration on the severity of joint and skin inflammation in patients with active Psoriatic Arthritis. Secondary objectives are to determine whether short-term liraglutide administration in patients with active psoriatic arthritis will 1) modify the degree of impaired glucose tolerance, underlying b-cell function and cardiovascular risk factor profiles, 2) improve patient-centered outcomes such as quality of life and functionality, 3) modify specific sub-populations of T-cells and affect their differentiation and activation, and 4) modify activation of circulating immune cells, pro-inflammatory cytokines, and hormones. Design: Double-blind, randomized, placebo-controlled trial, Phase II. Patient population: 34 patients between with active Psoriatic Arthritis meeting CASPAR (ClASsification criteria for Psoriatic ARthritis). Intervention: Participants will be randomized (1:1) to liraglutide (1.2 mg sc daily) or to placebo (sc daily) for 12 weeks. Endpoints: The primary endpoint of this study will be the proportion of patients who experience a 20% ACR (American College of Rheumatology) improvement response following liraglutide therapy as compared to placebo.
Interventions
DRUGliraglutide
Liraglutide 0.6mg sc daily for 1 week, 1.2mg sc daily for 11 weeks
OTHERPlacebo
Placebo sc daily for 12 weeks, volume titration at week 2 to mirror liraglutide arm
Sponsors
Novo Nordisk A/S
University Health Network, Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients with active psoriatic arthritis (3 tender and swollen joints) meeting CASPAR study group criteria
Exclusion criteria
* BMI \> 35 kg/m2 * Uncontrolled diabetes, HbA1c \> 10.5% * Current biological treatment for any inflammatory disorder within the past three months * renal dysfunction (eGFR \< 50 ml/min/1.73m or macroalbuminuria \>300mg) * hepatic dysfunction (AST (aspartate aminotransferase), ALT (alanine aminotransferase), Total bilirubin \> 3 times upper limit of normal) * history of pancreatitis or personal or family history of medullary thyroid cancer, c-cell hyperplasia, or MEN-2 syndrome * current pregnancy or current breast feeding * use of DPP-4 (dipeptidyl peptidase-4 inhibitor) or GLP-1 receptor agonist within 2 months (washout is permitted) * drug or alcohol dependence * resting tachycardia \> 100 bpm or conduction abnormalities associated with tachycardia * current enrollment in any other clinical trial * symptomatic gastroparesis * concomitant serious medical conditions * all medication for the treatment of Psoriatic Arthritis such as MTX (methotrexate) \< 25 mg, LFN (leflunomide) \< 20 mg, and NSAIDs (non-steroidal anti-inflammatory drugs) will have been used at stable doses for at least 4 weeks, having been initiated at least 3 months prior to study start (8 weeks before screening, 4 weeks before baseline) for MTX and LFN and at least 4 weeks for NSAIDs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The change in the proportion of patients achieving an ACR 20% improvement response in patients with psoriatic arthritis receiving liraglutide for 12 weeks compared to placebo | Baseline to 12 weeks, liraglutide compared to placebo | Proportion of patients achieving an ACR (American College of Rheumatology) 20% improvement response. ACR 20 is a composite rheumatological endpoint which includes swollen joint count, tender joint count, pain, physician global assessment, patient global assessment, HAQ (health assessment questionnaire), CRP (c reactive protein). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The change in the psoriasis area and severity index (PASI) in patients with psoriatic arthritis receiving liraglutide for 12 weeks compared to those receiving placebo | Baseline to 12 weeks | — |
| The change in quality of life measured by validated quality of life questionnaires in patients with psoriatic arthritis receiving liraglutide for 12 weeks compared to those receiving placebo | Baseline to 12 weeks | — |
| The effect(s) of liraglutide on cardiovascular disease risk factors in patients with psoriatic arthritis receiving liraglutide for 12 weeks compared to those receiving placebo | Baseline to 12 weeks | Cardiovascular disease risk factors (Systolic blood pressure, cholesterol profiles, CRP, body weight, waist circumference) |
| The effect(s) of liraglutide on the enumeration of circulating T-cell subpopulations, and on activation of circulating T-cell subpopulations | Baseline to 12 weeks | Multi-parameter phospho flow cytometry analysis of T-cell differentiation and activation of peripheral blood |
| The change in glucose tolerance in patients with psoriatic arthritis with glucose intolerance at baseline who receive liraglutide for 12 weeks compared to those receiving placebo | Baseline to 12 weeks | — |
Other
| Measure | Time frame |
|---|---|
| The effect of liraglutide on levels of infiltrating dermal T cells and cytokines in psoriatic skin plaques from patients with psoriatic arthritis receiving liraglutide therapy for 12 weeks compared to those receiving placebo | Baseline to 12 weeks |
Countries
Canada
Outcome results
None listed