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

• ClinicalTrials.gov Identifier: NCT02559622
• Recruitment Status: Completed
• First Posted: September 24, 2015
• Results First Posted: July 13, 2017
• Last Update Posted: July 13, 2017
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Psoriasis	Drug: Secukinumab; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 151 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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).
• Study Start Date: April 2014
• Actual Primary Completion Date: April 2016
• Actual Study Completion Date: April 2016

Arms and Interventions

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 Name: 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; 150 mg secukinumab; Other Name: AIN457
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
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 150 mg secukinumab

Outcome Measures

Primary Outcome Measures :

1. Flow Mediated Dilation (FMD) at Week 12 Followed by Secukinumab 300 mg vs Pooled Placebo Treatment [ Time Frame: Week 12 ]
   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.

Secondary Outcome Measures :

1. Change From Baseline in Flow Mediated Dilation (FMD) at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
2. Change From Baseline in Aortic Augmentation Index at Heart Rate of 75 (AIx-75) at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
3. Change From Baseline in Pulse Wave Velocity (PWV) at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
4. Change From Baseline in Average Wall Area Assessed as a Measure of Total Plaque Burden at Week 12 [ Time Frame: Baseline, 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.
5. Change From Baseline in Average Wall Area Assessed as a Measure of Total Plaque Burden at Week 52 [ Time Frame: Baseline, 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.
6. Change From Baseline in High Sensitivity C-reactive Protein (hsCRP) at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
7. Change From Baseline in S-100 Protein B (Total) at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
8. 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 [ Time Frame: Baseline, 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.
9. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
10. Change From Baseline in Fasting Insulin at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
11. Change From Baseline in Homeostatic Model Assessment (HOMA) Beta-cell Function at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
12. Change From Baseline in Homeostatic Model Assessment (HOMA) Insulin Resistance at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
13. Change From Baseline in Hemoglobin A1c (Glycated Hemoglobin) at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
14. Change From Baseline in Sex Hormone-binding Globulin (SHBG) at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
15. 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 [ Time Frame: Baseline, 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.
16. Change From Baseline in Adiponectin at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.
17. Change From Baseline in Leptin at Week 4, 12, 24 and 52 [ Time Frame: Baseline, 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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

Germany

Novartis Investigative Site

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

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02559622
• Other Study ID Numbers: CAIN457ADE02
• First Posted: September 24, 2015
• Results First Posted: July 13, 2017
• Last Update Posted: July 13, 2017
• Last Verified: April 2017

Additional relevant MeSH terms:

Psoriasis; Skin Diseases, Papulosquamous; Skin Diseases; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs