Dipeptidyl Peptidase-4 Inhibition in Psoriasis Patients With Diabetes (DIP): A Randomized Clinical Trial.

NCT01991197 | Completed Phase 2 Results DMC

• 2 other identifiers: DPIDM-2012-012012-005505-51
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

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.

Conditions

Psoriasis; Type 2 Diabetes Mellitus

Keywords

Psoriasis; Type 2 Diabetes; Dipeptidyl peptidase-4 inhibition; Sitagliptin; Gliclazide; Psoriasis area and severity index

Outcome Measures

Primary Outcomes (1)

• 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.

  Psoriasis area and severity index (0-72), higher scores worse outcome

  16 weeks

Secondary Outcomes (13)

• The Number of Patricipants in the Sitagliptin and Gliclazide Arms With Adverse Events at 32 Weeks.

  32 weeks

• The Change in Quality of Life Scores From Baseline to 16 Weeks in the Sitagliptin and Gliclazide Arms.

  16 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

Other Outcomes (2)

• The Effect of Treatment With Sitagliptin and With Gliclazide From Baseline to 16 Weeks on the Change in Interleukin-17 Levels in the Skin (in a Sub-group of Participants Willing to Undergo Skin Biopsies).

  16 weeks

• The Effect of Treatment With Sitagliptin and With Gliclazide From Baseline to 16 Weeks on the Change in Dipeptidyl Peptidase-4 Levels in the Skin (in a Sub-group of Participants Willing to Undergo Skin Biopsies).

  16 weeks

Study Arms (2)

Sitagliptin

EXPERIMENTAL

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.

Drug: Sitagliptin; Drug: Gliclazide matched placebo capsule

Gliclazide

ACTIVE COMPARATOR

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.

Drug: Sitagliptin; Drug: Gliclazide; Drug: Sitagliptin matched placebo

Interventions

Sitagliptin DRUG

Week 0-16: Two 50mg tablets (or one 50mg tablet for participants with moderate kidney disease) once daily for 16 weeks during the double-blind phase. Week 16-32: Then two 50mg tablets (or one 50mg tablet for participants with moderate kidney disease) once daily for 16 weeks during the open-label phase of the trial.

Also known as: Januvia®

Gliclazide; Sitagliptin

Gliclazide DRUG

Double-blind phase (week 0-16): One 80mg capsule once daily for 4 weeks. The if no severe hypoglycaemic episodes one 80mg capsule twice daily for 4 weeks. Then if no severe hypoglycaemic episodes two 80mg capsules twice daily for 8 weeks.

Also known as: Diamicron

Gliclazide

Sitagliptin matched placebo DRUG

Week 0-16: Two tablets (or one tablet for those with moderate kidney disease) daily for 16 weeks during the double-blind phase.

Gliclazide

Gliclazide matched placebo capsule DRUG

Double-blind phase (week 0-16): One capsule daily for 4 weeks. Then if no severe hypoglycaemic episodes one capsule twice daily for 4 weeks. Then if no severe hypoglycaemic episodes two capsules twice daily for 8 weeks.

Sitagliptin

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University College Dublin: lead

Study Sites (2)

The Adelaide and Meath Hospital

Dublin, Ireland

Location

UCD Clinical Research Centre, St Vincent's University Hospital,

Dublin, Ireland

Location

Related Publications (25)

• Schon MP, Boehncke WH. Psoriasis. N Engl J Med. 2005 May 5;352(18):1899-912. doi: 10.1056/NEJMra041320. No abstract available.

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• Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009 Jul 30;361(5):496-509. doi: 10.1056/NEJMra0804595. No abstract available.

  PMID: 19641206 BACKGROUND

• Novelli M, Savoia P, Fierro MT, Verrone A, Quaglino P, Bernengo MG. Keratinocytes express dipeptidyl-peptidase IV (CD26) in benign and malignant skin diseases. Br J Dermatol. 1996 Jun;134(6):1052-6.

  PMID: 8763423 BACKGROUND

• van Lingen RG, van de Kerkhof PC, Seyger MM, de Jong EM, van Rens DW, Poll MK, Zeeuwen PL, van Erp PE. CD26/dipeptidyl-peptidase IV in psoriatic skin: upregulation and topographical changes. Br J Dermatol. 2008 Jun;158(6):1264-72. doi: 10.1111/j.1365-2133.2008.08515.x. Epub 2008 Mar 29.

  PMID: 18384439 BACKGROUND

• Thielitz A, Reinhold D, Vetter R, Bank U, Helmuth M, Hartig R, Wrenger S, Wiswedel I, Lendeckel U, Kahne T, Neubert K, Faust J, Zouboulis CC, Ansorge S, Gollnick H. Inhibitors of dipeptidyl peptidase IV and aminopeptidase N target major pathogenetic steps in acne initiation. J Invest Dermatol. 2007 May;127(5):1042-51. doi: 10.1038/sj.jid.5700439. Epub 2006 Jun 15.

  PMID: 16778789 BACKGROUND

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  PMID: 21404914 BACKGROUND

• Nishioka T, Shinohara M, Tanimoto N, Kumagai C, Hashimoto K. Sitagliptin, a dipeptidyl peptidase-IV inhibitor, improves psoriasis. Dermatology. 2012;224(1):20-1. doi: 10.1159/000333358. Epub 2011 Nov 1.

  PMID: 22056790 BACKGROUND

• Heydendael VM, Spuls PI, Opmeer BC, de Borgie CA, Reitsma JB, Goldschmidt WF, Bossuyt PM, Bos JD, de Rie MA. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med. 2003 Aug 14;349(7):658-65. doi: 10.1056/NEJMoa021359.

  PMID: 12917302 BACKGROUND

• Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, Guzzo C, Xia Y, Zhou B, Li S, Dooley LT, Goldstein NH, Menter A; ACCEPT Study Group. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010 Jan 14;362(2):118-28. doi: 10.1056/NEJMoa0810652.

  PMID: 20071701 BACKGROUND

• Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003 Jun;111(12):1805-12. doi: 10.1172/JCI18921. No abstract available.

  PMID: 12813013 BACKGROUND

• Hattori S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr J. 2011;58(1):69-73. doi: 10.1507/endocrj.k10e-382. Epub 2010 Dec 28.

  PMID: 21206136 BACKGROUND

• Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Ragonesi PD, Querci F, Franzetti IG, Gadaleta G, Ciccarelli L, Piccinni MN, D'Angelo A, Cicero AF. Effects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients. Metabolism. 2010 Jun;59(6):887-95. doi: 10.1016/j.metabol.2009.10.007. Epub 2009 Dec 16.

  PMID: 20015525 BACKGROUND

• Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, Musser BJ, Davies MJ, Kaufman KD, Goldstein BJ. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord. 2010 Apr 22;10:7. doi: 10.1186/1472-6823-10-7.

  PMID: 20412573 BACKGROUND

• Lamanna C, Monami M, Bartoli N, Zannoni S, Mannucci E. Dipeptidyl peptidase- 4 inhibitors and cardiovascular events: a protective effect? Diabetologia. 2011;54:S109.

  BACKGROUND

• Chodorowska G, Wojnowska D, Juszkiewicz-Borowiec M. C-reactive protein and alpha2-macroglobulin plasma activity in medium-severe and severe psoriasis. J Eur Acad Dermatol Venereol. 2004 Mar;18(2):180-3. doi: 10.1111/j.1468-3083.2004.00863.x.

  PMID: 15009298 BACKGROUND

• Gisondi P, Malerba M, Malara G, Puglisi Guerra A, Sala R, Radaeli A, Calzavara-Pinton P, Girolomoni G. C-reactive protein and markers for thrombophilia in patients with chronic plaque psoriasis. Int J Immunopathol Pharmacol. 2010 Oct-Dec;23(4):1195-202. doi: 10.1177/039463201002300423.

  PMID: 21244768 BACKGROUND

• Nisa N, Ahmed Q. High-sensitivity C-reactive protein in psoriasis. Int J Dermatol. 2012 Nov;51(11):1393-4. doi: 10.1111/j.1365-4632.2010.04761.x. Epub 2011 May 30. No abstract available.

  PMID: 21623773 BACKGROUND

• Mittal R, Malhotra S, Pandhi P, Kaur I, Dogra S. Efficacy and safety of combination Acitretin and Pioglitazone therapy in patients with moderate to severe chronic plaque-type psoriasis: a randomized, double-blind, placebo-controlled clinical trial. Arch Dermatol. 2009 Apr;145(4):387-93. doi: 10.1001/archdermatol.2009.5.

  PMID: 19380660 BACKGROUND

• Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care. 2010 Feb;33(2):428-33. doi: 10.2337/dc09-1499. No abstract available.

  PMID: 20103558 BACKGROUND

• Hossler EW, Maroon MS, Mowad CM. Gastric bypass surgery improves psoriasis. J Am Acad Dermatol. 2011 Jul;65(1):198-200. doi: 10.1016/j.jaad.2010.01.001. Epub 2010 Jul 22.

  PMID: 20655127 BACKGROUND

• Hogan AE, Tobin AM, Ahern T, Corrigan MA, Gaoatswe G, Jackson R, O'Reilly V, Lynch L, Doherty DG, Moynagh PN, Kirby B, O'Connell J, O'Shea D. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia. 2011 Nov;54(11):2745-54. doi: 10.1007/s00125-011-2232-3. Epub 2011 Jul 9.

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• Ahern T, Tobin AM, Corrigan M, Hogan A, Sweeney C, Kirby B, O'Shea D. Glucagon-like peptide-1 analogue therapy for psoriasis patients with obesity and type 2 diabetes: a prospective cohort study. J Eur Acad Dermatol Venereol. 2013 Nov;27(11):1440-3. doi: 10.1111/j.1468-3083.2012.04609.x. Epub 2012 Jun 13.

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  PMID: 18539916 BACKGROUND

• Tobin AM, personal communication.

  BACKGROUND

Related Links

• A web-based randomization plan generator.

MeSH Terms

Conditions

Psoriasis; Diabetes Mellitus, Type 2

Interventions

Sitagliptin Phosphate; Gliclazide

Condition Hierarchy (Ancestors)

Skin Diseases, Papulosquamous; Skin Diseases; Skin and Connective Tissue Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds

Limitations and Caveats

Despite a significant effort to recruit eligible patients (89 screened), we were unable to meet the required target of 40 and recruited 20 participants. Therefore the study was underpowered to achieve its endpoints.

Results Point of Contact

• Title: Dr Maeve Lynch
• Organization: Clinical Research Centre, St Vincent's University Hospital, Dublin, Ireland

maeve.lynch2@hse.ie

Study Officials

• Brian Kirby, MBBChBAOMD

  UCD Clinical Research Centre, St Vincent's University Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD student, Medical Doctor

Study Record Dates

• First Submitted: November 10, 2013
• First Posted: November 25, 2013
• Study Start: April 1, 2014
• Primary Completion: January 1, 2016
• Study Completion: January 1, 2016
• Last Updated: May 14, 2020
• Results First Posted: May 14, 2020

Record last verified: 2020-05

Locations

IE (2)