Dipeptidyl Peptidase-4 Inhibition in Psoriasis Patients With Diabetes (DIP): A Randomized Clinical Trial.
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- University College Dublin
- Enrollment
- 20
- Locations
- 2
- Primary Endpoint
- The Change in the Psoriasis Area and Severity Index (PASI) From Baseline to 16 Weeks in Psoriasis Patients With Type 2 Diabetes Treated With Sitagliptin Compared to Patients Treated With Gliclazide.
Study Overview
Brief Summary
The primary purpose of this study is to determine if sitagliptin (Januvia®) improves psoriasis severity after 16 weeks of treatment in 20 participants with both psoriasis and type 2 diabetes mellitus. We will compare the change in psoriasis severity in 20 participants treated with Januvia® to 20 participants treated with 16 weeks of a comparator drug (gliclazide, Diamicron®). Participants will be recruited from two centres and after a 4 week washout period will be followed prospectively for 36 weeks. Participants will be stratified by centre, psoriasis severity and obesity status after which they will be randomly allocated to Arm A or Arm B. Participants will be treated with either Januvia® and Diamicron® matched placebo capsules (Arm A), or Diamicron® and Januvia® matched placebo tablets (Arm B) for 16 weeks and then proceed to an open-label phase where all participants will receive Januvia® for a further 16 weeks.
Both the research participants and the investigators will be unaware of the trial arm to which the research participant has been allocated (double-blind study). Research participants will be prohibited from making any changes to the dose of medications used to treat psoriasis. If a participant's plasma glycated haemoglobin level (HbA1c) (reflects a participant's glucose control over the previous 3 months) is above 64mmol/mol eight weeks after commencing one of the study investigational medicinal products (IMPs) insulin therapy will be used to improve glycaemic control.
Participants will be assessed at 9 study visits over 40 weeks. Participants will complete questionnaires, have a medical history recorded and physical examination, blood sampling and skin biopsies taken (in a small number of willing participants at 3 visits).
The following endpoints will be analysed:
Changes in psoriasis severity at 16 and 32 weeks; changes in validated quality of life scores; incidence of adverse events; incidence of discontinuation of one of the study IMPs, time to relapse of psoriasis; changes in cardiovascular disease risk factor profiles; changes in cytokines, hormones, expression of immune proteins in blood and skin biopsies; and genetic profiles that predicts best response to sitagliptin therapy.
We hypothesize that sitagliptin therapy decreases psoriasis severity.
Detailed Description
Background:
Psoriasis is a chronic, autoimmune skin disease affecting approximately 2% of the world's population. It is characterised by keratinocyte hyperproliferation, by aberrant keratinocyte differentiation and by cutaneous inflammation.
Dipeptidyl peptidase-4 (DPP-4) is expressed on keratinocytes and its activity is upregulated in psoriasis. DPP-4 inhibition suppresses keratinocyte proliferation and restores partially keratinocyte differentiation. The main site of DPP-4 activity is cluster of differentiation antigen 26 (CD26). CD26 is a marker of T cell activation and is a key molecule in the pathogenesis of autoimmune diseases. One case of DPP-4 inhibitor therapy improving psoriasis severity has been reported.
Agents used to treat psoriasis target commonly the underlying inflammation. C-reactive protein (CRP) is a sensitive, systemic marker of inflammation. In people with type 2 diabetes (T2DM) DPP-4 inhibitor therapy decreases CRP concentrations. Serum CRP concentrations correlate with psoriasis severity and interventions that decrease the CRP concentration may decrease also psoriasis severity. Medications that improve insulin resistance may decrease also systemic inflammation and improve psoriasis. We have shown previously, in psoriasis patients without T2DM (both lean and obese), that the fasting insulin concentration and the homeostatic model of insulin resistance (measures of insulin resistance) correlate strongly with the psoriasis area and severity index (PASI, a measure of psoriasis severity: r=0.48, p<0.001; r=0.49, p<0.001).
DPP-4 inhibitors prevent also the degradation of insulin secretagogues, such as glucagon-like peptide-1 (GLP-1), thereby ameliorating hyperglycaemia without causing hypoglycaemia. Due to this effect DPP-4 inhibitors are effective for the treatment of T2DM. Other interventions which increase GLP-1 receptor activation, such as roux-en-Y gastric bypass surgery and GLP-1 analogue therapy, can improve also psoriasis severity.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •People who satisfy all of the following may be included in the study:
- •Have a diagnosis of generalized chronic plaque and/or guttate psoriasis;
- •Are male or female aged between 18 and 75 years inclusive;
- •Have a psoriasis area and severity index (PASI) greater than 7;
- •Have a diagnosis of type 2 diabetes;
- •Have a glycated haemoglobin (HbA1c) level between 48mmol/mol and 69mmol/mol;
- •Are able and willing to stop sulphonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor and glucagon-like peptide-1 (GLP-1) analogue therapy for the duration of the study;
- •Have a negative pregnancy test at screening (women of child bearing potential only); and
- •Are willing to voluntarily sign a statement of informed consent to participate in the study.
Exclusion Criteria
- •People with any of the following conditions will be excluded from the study:
- •Allergy or hypersensitivity to sitagliptin (Januvia®) or gliclazide (Diamicron®);
- •Current or recent (within 8 weeks) receipt of phototherapy;
- •Type 1 diabetes;
- •Severe kidney disease as defined by a previous diagnosis of chronic kidney disease in the presence of an estimated glomerular filtration rate (eGFR) of less than 30ml/min/1.73 m2;
- •Severe heart disease as defined by a previous diagnosis of heart disease and a left ventricular ejection fraction which is known to be less than 35% (as measured by echocardiogram or cardiac catheterisation study);
- •Severe lung disease as defined by a previous diagnosis of chronic lung disease and a forced expiratory volume in 1 second (FEV1) or a forced vital capacity (FVC) that is known to be less than 50% that which would be estimated for a person of that age and gender;
- •Severe liver disease as defined by a previous diagnosis of chronic liver disease in the presence of an alanine transferase concentration greater than 150 international units (IU)/L (greater than three times the upper limit of the normal reference range);
- •Any other contraindications, as stated in the SPCs for sitagliptin (Januvia®) or gliclazide (Diamicron®);
- •Female patients of child bearing potential who are pregnant, breastfeeding, or unwilling to practice an acceptable barrier and/or hormonal method of contraception during participation in the study - abstinence will be permitted only if it is in keeping with a person's lifestyle;
- •Any clinically significant chronic disease that might, in the opinion of the investigator, interfere with the evaluations or preclude completion of the trial;
- •Any current or recent (within the past 4 weeks) acute serious illness, acute psychiatric illness or severe uncontrolled/unstable illness;
- •Previous randomisation into this study;
- •Concurrent participation in another clinical trial; and
- •Participation in another clinical trial during the twelve weeks prior to study entry (i.e.
- •screening visit).
Arms & Interventions
Sitagliptin
Double blind phase (week 0-16):
Sitagliptin two 50mg tablets (or one 50mg in participants with moderate kidney disease) once daily for 16 weeks.
Placebo Comparator: Gliclazide matched placebo One gliclazide matched placebo capsule daily for 4 weeks. If no severe hypoglycaemic episodes one gliclazide matched placebo capsule twice daily for 4 weeks. If no severe hypoglycaemic episodes two gliclazide matched placebo capsules twice daily for 8 weeks.
Open-label phase (week 16-32):
Sitagliptin two 50mg tablets (or one 50mg in participants with moderate kidney disease) once daily for 16 weeks.
Intervention: Sitagliptin (Drug)
Sitagliptin
Double blind phase (week 0-16):
Sitagliptin two 50mg tablets (or one 50mg in participants with moderate kidney disease) once daily for 16 weeks.
Placebo Comparator: Gliclazide matched placebo One gliclazide matched placebo capsule daily for 4 weeks. If no severe hypoglycaemic episodes one gliclazide matched placebo capsule twice daily for 4 weeks. If no severe hypoglycaemic episodes two gliclazide matched placebo capsules twice daily for 8 weeks.
Open-label phase (week 16-32):
Sitagliptin two 50mg tablets (or one 50mg in participants with moderate kidney disease) once daily for 16 weeks.
Intervention: Gliclazide matched placebo capsule (Drug)
Gliclazide
Double-blind phase (week 0-16):
Gliclazide 80mg once daily for 4 weeks Then if no severe hypoglycaemic episodes increase to Gliclazide 80mg twice daily for 4 weeks.
Then if no severe hypoglycaemic episodes increase to Gliclazide 160mg twice daily for 8 weeks Placebo Comparator: Sitagliptin matched placebo Two tablets (or one tablet in participants with moderate kidney disease) once daily for 16 weeks.
Open-label phase (week 16-32):
Sitagliptin two 50mg tablets (or one 50mg in participants with moderate kidney disease) once daily for 16 weeks.
Intervention: Sitagliptin (Drug)
Gliclazide
Double-blind phase (week 0-16):
Gliclazide 80mg once daily for 4 weeks Then if no severe hypoglycaemic episodes increase to Gliclazide 80mg twice daily for 4 weeks.
Then if no severe hypoglycaemic episodes increase to Gliclazide 160mg twice daily for 8 weeks Placebo Comparator: Sitagliptin matched placebo Two tablets (or one tablet in participants with moderate kidney disease) once daily for 16 weeks.
Open-label phase (week 16-32):
Sitagliptin two 50mg tablets (or one 50mg in participants with moderate kidney disease) once daily for 16 weeks.
Intervention: Gliclazide (Drug)
Gliclazide
Double-blind phase (week 0-16):
Gliclazide 80mg once daily for 4 weeks Then if no severe hypoglycaemic episodes increase to Gliclazide 80mg twice daily for 4 weeks.
Then if no severe hypoglycaemic episodes increase to Gliclazide 160mg twice daily for 8 weeks Placebo Comparator: Sitagliptin matched placebo Two tablets (or one tablet in participants with moderate kidney disease) once daily for 16 weeks.
Open-label phase (week 16-32):
Sitagliptin two 50mg tablets (or one 50mg in participants with moderate kidney disease) once daily for 16 weeks.
Intervention: Sitagliptin matched placebo (Drug)
Outcomes
Primary Outcomes
The Change in the Psoriasis Area and Severity Index (PASI) From Baseline to 16 Weeks in Psoriasis Patients With Type 2 Diabetes Treated With Sitagliptin Compared to Patients Treated With Gliclazide.
Time Frame: 16 weeks
Psoriasis area and severity index (0-72), higher scores worse outcome
Secondary Outcomes
- The Change in Quality of Life Scores From Baseline to 16 Weeks in the Sitagliptin and Gliclazide Arms.(16 weeks)
- The Change in Levels of Total Cholesterol From Baseline to 16 Weeks in the Sitagliptin and Gliclazide Arms.(16 weeks)
- The Effects of Treatment With Sitagliptin and Treatment With Gliclazide From Baseline to 16 Weeks on Serum Levels Interleukin-23.(16 weeks)
- The Effects of Treatment With Sitagliptin and Treatment With Gliclazide From Baseline to 16 Weeks on Serum Levels Interleukin-17.(16 weeks)
- The Number of Patricipants in the Sitagliptin and Gliclazide Arms With Adverse Events at 32 Weeks.(32 weeks)
- The Effects of Treatment With Sitagliptin and Treatment With Gliclazide on Other Efficacy Endpoints.(16 weeks)
- The Change in Levels of High Sensitivity C-reactive Protein From Baseline to 16 Weeks in the Sitagliptin and Gliclazide Arms.(16 weeks)
- The Effects of Treatment With Sitagliptin and Treatment With Gliclazide on the Serum Cytokine Tumour Necrosis Factor Alpha.(16 weeks)
- The Change in PASI From Baseline to 32 Weeks in Psoriasis Patients With Type 2 Diabetes Treated With Sitagliptin Compared to Patients Treated With Gliclazide.(baseline and 32 weeks)
- The Change in Weight From Baseline to 16 Weeks in the Sitagliptin and Gliclazide Arms.(16 weeks)
- The Change in Levels of Systolic Blood Pressure From Baseline to 16 Weeks in the Sitagliptin and Gliclazide Arms.(16 weeks)
- The Change in Levels of Serum Glucose From Baseline to 16 Weeks in the Sitagliptin and Gliclazide Arms.(16 weeks)
- The Effects of Treatment With Sitagliptin and Treatment With Gliclazide on the Change in Serum Leptin From Baseline to 16 Weeks.(16 weeks)
Investigators
Maeve Lynch
MD student, Medical Doctor
University College Dublin