Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated With Secukinumab (CARIMA)

A Randomized, Double-blind, Placebo-controlled, Multicenter, Exploratory Evaluation of Surrogate Markers of Cardiovascular Risk in Patients With Active Chronic Plaque-type Psoriasis Treated for up to 52 Weeks With Subcutaneous (s.c.) Secukinumab (300 mg or 150 mg).

The purpose of this study was to explore the effect of treatment with 300 mg or with 150 mg secukinumab (administered weekly for 4 weeks followed by four-weekly administration) on endothelial dysfunction and arterial stiffness after 12 weeks and for up to 52 weeks in subjects with chronic plaque-type psoriasis. Furthermore soluble biomarkers were assessed to evaluate the influence of secukinumab on cardiovascular risk. Magnetic resonance imaging (MRI) was performed in a sub-population to assess the treatment effect on arterial vessel wall morphometry in atherosclerosis prone vascular beds.

Study Overview

• Status: Completed
• Conditions: Psoriasis
• Intervention / Treatment: Drug: Secukinumab; Drug: Secukinumab; Other: Placebo; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 151
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Augsburg, Germany, 86179
    • Novartis Investigative Site
  • Berlin, Germany, 10789
    • Novartis Investigative Site
  • Berlin, Germany, 13187
    • Novartis Investigative Site
  • Bielefeld, Germany, 33647
    • Novartis Investigative Site
  • Bochum, Germany, 44791
    • Novartis Investigative Site
  • Bonn, Germany, 53105
    • Novartis Investigative Site
  • Darmstadt, Germany, 64283
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Duisburg, Germany, 47166
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Freiburg, Germany, 79104
    • Novartis Investigative Site
  • Gera, Germany, 07548
    • Novartis Investigative Site
  • Hamburg, Germany, 20354
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Homburg, Germany, 66421
    • Novartis Investigative Site
  • Langenau, Germany, 89129
    • Novartis Investigative Site
  • Lubeck, Germany, 23538
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • München, Germany, 81675
    • Novartis Investigative Site
  • Stade, Germany, 21682
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Chronic moderate to severe plaque type psoriasis for at least 6 months prior to randomization with a Psoriasis Area and Severity Index (PASI) score ≥ 10 at randomization.
• Inadequate response, intolerance or contraindication to cyclosporine, methotrexate and psoralen plus ultraviolet A light treatment (PUVA) as documented in the patient's medical history or reported by the patient or determined by the investigator at screening. Relative contraindications such as interference of patient's lifestyle with the treatment are accepted.

Key Exclusion Criteria:

• Forms of psoriasis other than chronic plaque-type (e.g., pustular, erythrodermic and guttata psoriasis) at screening or randomization.
• Ongoing use of prohibited psoriasis and non-psoriasis treatments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 300 mg secukinumab; 300 mg secukinumab every week for 4 weeks followed by 300 mg secukinumab every 4 weeks until week 48 (last injection)	Drug: Secukinumab; 300 mg secukinumab; Other Names: AIN457; Drug: Secukinumab; 150 mg secukinumab; Other Names: AIN457
Experimental: 150 mg secukinumab; 150 mg secukinumab every week for 4 weeks followed by 150 mg secukinumab every 4 weeks until week 48 (last injection)	Drug: Secukinumab; 300 mg secukinumab; Other Names: AIN457; Drug: Secukinumab; 150 mg secukinumab; Other Names: AIN457
Other: Placebo followed by 300 mg secukinumab; Placebo until week 12 followed by 300 mg secukinumab every week for 4 weeks followed by 300 mg secukinumab every 4 weeks until week 48 (last injection)	Other: Placebo; Placebo followed by 300 mg secukinumab; Other: Placebo; Placebo followed by 150 mg secukinumab
Other: Placebo followed by 150 mg secukinumab; Placebo until week 12 followed by 150 mg secukinumab every week for 4 weeks followed by 150 mg secukinumab every 4 weeks until week 48 (last injection)	Other: Placebo; Placebo followed by 300 mg secukinumab; Other: Placebo; Placebo followed by 150 mg secukinumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow Mediated Dilation (FMD) at Week 12 Followed by Secukinumab 300 mg vs Pooled Placebo Treatment	Flow Mediated Dilation (FMD) is non-invasive method evaluated by Doppler Ultrasound test, to assess endothelial function. FMD was calculated as the percent maximal deviation from the baseline arterial diameter (D):FMD = 100*[(D maximum - D baseline) / D baseline]. Here, arterial diameter (brachial artery) was measured at rest (1 minute), during inflation of the distal cuff to 100 millimeter of mercury (mmHg) for 4.5 minutes and for 4.5 minutes following deflation.	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Flow Mediated Dilation (FMD) at Week 4, 12, 24 and 52	FMD is non-invasive method evaluated by Doppler Ultrasound test, to assess endothelial function. FMD was calculated as the percent maximal deviation from the baseline arterial diameter (D):FMD = 100*[(D maximum - D baseline) / D baseline]. Here, arterial diameter (brachial artery) was measured at rest (1 minute), during inflation of the distal cuff to 100 mmHg for 4.5 minutes and for 4.5 minutes following deflation. A positive change in FMD constitutes an improvement in endothelial function.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Aortic Augmentation Index at Heart Rate of 75 (AIx-75) at Week 4, 12, 24 and 52	Pulse wave analysis was performed on the central aortic pressure waveform as derived by SphygmoCor XCEL from the brachial pressure waveform recorded in a partially-inflated blood pressure cuff around the upper arm. The waveform derivation employs a validated generalized transfer function to convert a brachial waveform to a central waveform and has been shown to produce measurement results corresponding to measurements using intra-arterial pressure catheters. The augmentation index is derived from the waveform by determining the percentage of the central pulse pressure during systole due to wave reflection. AIx was heart-rate corrected to calculate the AIx at a heart rate of 75 bpm, i.e. AIx-75.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Pulse Wave Velocity (PWV) at Week 4, 12, 24 and 52	Regional arterial pulse wave velocity (PWV) was directly related to arterial stiffness and was defined as the time it takes for the blood pressure wave to travel from a proximal site to a distal site (relative to the heart) divided by the distance (PWV = ∆distance/∆time [m/s]). The foot of the arterial pulse wave was being recorded by using the SphygmoCor XCEL device. XCEL simultaneously measures the pressure waveform at the femoral site (using a partially inflated custom blood pressure cuff) and the carotid site (using hand-held applanation tonometry). The foot-to-foot time between the two pressure waveforms was the time interval used in the PWV calculation.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Average Wall Area Assessed as a Measure of Total Plaque Burden at Week 12	Magnetic resonance imaging (MRI) was used to evaluate vessel wall morphometry to determine plaque burden. As a measure of plaque burden, average wall area was computed by subtracting vessel lumen area from total vessel area. Exploratory 3.0 Tesla MRI technique was applied to assess structure and function of the carotid and the aorta. A 2D axial dark blood T1, T2, proton density weighted spin echo based images and time of flight images were acquired from the bilateral carotid arteries as well as the descending aorta.	Baseline, Week 12
Change From Baseline in Average Wall Area Assessed as a Measure of Total Plaque Burden at Week 52	Magnetic resonance imaging (MRI) was used to evaluate vessel wall morphometry to determine plaque burden. As a measure of plaque burden, average wall area was computed by subtracting vessel lumen area from total vessel area. Exploratory 3.0 Tesla MRI technique was applied to assess structure and function of the carotid and the aorta. A 2D axial dark blood T1, T2, proton density weighted spin echo based images and time of flight images were acquired from the bilateral carotid arteries as well as the descending aorta.	Baseline, Week 52
Change From Baseline in High Sensitivity C-reactive Protein (hsCRP) at Week 4, 12, 24 and 52	High sensitivity C-reactive protein (hsCRP), a soluble biomarker of systemic inflammation was determined in fasting blood samples to evaluate the effect of secukinumab on systemic inflammation.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in S-100 Protein B (Total) at Week 4, 12, 24 and 52	S100 calcium-binding protein B (S100B-protein), a soluble biomarker of systemic inflammation was determined in fasting blood samples to evaluate the effect of secukinumab on systemic inflammation.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Chemokine (C-c Motif) Ligand 5 (CCL5), Monocyte Chemoattractant Protein 1 (MCP-1) and Macrophage Inflammatory Proteins (MIP) 1 Alpha and 1 Beta at Week 4, 12, 24 and 52	Chemokine (c-c motif) ligand 5 (CCL5), Monocyte chemoattractant protein 1 (MCP-1) and Macrophage inflammatory proteins (MIP) 1 alpha (1A) and 1 beta (1B), soluble biomarkers of systemic inflammation were determined in fasting blood samples to evaluate the effect of secukinumab on systemic inflammation.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 4, 12, 24 and 52	Fasting plasma glucose (FPG), a soluble biomarker of Dysglycemia was determined in fasting blood samples to evaluate the effect of secukinumab on systemic inflammation.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Fasting Insulin at Week 4, 12, 24 and 52	Fasting Insulin, a soluble biomarker of Dysglycemia was determined in fasting blood samples to evaluate the effect of secukinumab on Dysglycemia.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Homeostatic Model Assessment (HOMA) Beta-cell Function at Week 4, 12, 24 and 52	Homeostatic Model Assessment (HOMA) beta-cell function, a soluble biomarker of Dysglycemia was determined in fasting blood samples to evaluate the effect of secukinumab on Dysglycemia.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Homeostatic Model Assessment (HOMA) Insulin Resistance at Week 4, 12, 24 and 52	HOMA insulin resistance, a soluble biomarker of Dysglycemia was determined in fasting blood samples to evaluate the effect of secukinumab on Dysglycemia.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Hemoglobin A1c (Glycated Hemoglobin) at Week 4, 12, 24 and 52	Hemoglobin A1c (glycated hemoglobin), a soluble biomarker of Dysglycemia was determined in fasting blood samples to evaluate the effect of secukinumab on Dysglycemia.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Sex Hormone-binding Globulin (SHBG) at Week 4, 12, 24 and 52	Sex hormone-binding globulin (SHBG), a soluble biomarker of Dysglycemia was determined in fasting blood samples to evaluate the effect of secukinumab on Dysglycemia.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Triglycerides, Total Cholesterol, Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL), Apolipoprotein A-1 (ApoA-1) and Apolipoprotein B (ApoB) at Week 4, 12, 24 and 52	Triglycerides, Total cholesterol, Low density lipoprotein (LDL), High density lipoprotein (HDL), Apolipoprotein A-1 (ApoA-1) and Apolipoprotein B (ApoB), soluble biomarkers of impaired lipid metabolism were determined in fasting blood samples to evaluate the effect of secukinumab on impaired lipid metabolism.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Adiponectin at Week 4, 12, 24 and 52	Adiponectin, a soluble biomarker of impaired lipid metabolism was determined in fasting blood samples to evaluate the effect of secukinumab on systemic inflammation.	Baseline, Week 4, 12, 24 and 52
Change From Baseline in Leptin at Week 4, 12, 24 and 52	Leptin, a soluble biomarker of impaired lipid metabolism was determined in fasting blood samples to evaluate the effect of secukinumab on systemic inflammation.	Baseline, Week 4, 12, 24 and 52

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: August 4, 2015
• First Submitted That Met QC Criteria: September 23, 2015
• First Posted (Estimate): September 24, 2015

Study Record Updates

• Last Update Posted (Actual): July 13, 2017
• Last Update Submitted That Met QC Criteria: April 19, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Skin Diseases, Papulosquamous; Psoriasis; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: CAIN457ADE02