Extended Release Niacin and Fenofibrate for the Treatment of Atherogenic Dyslipidemia in Obese Females

Study Overview
=================
Brief Summary
-----------------
Atherogenic Dyslipidemia (AD) is a risk-conferring lipid/lipoprotein profile that comprises a higher proportion of small LDL particles, reduced HDL-C, and increased triglycerides. It is characteristically seen in patients with obesity, metabolic syndrome, insulin resistance, and type 2 diabetes mellitus and has emerged as an important marker for the increased cardiovascular disease (CVD) risk observed in these populations. Optimal cardiovascular risk reduction in patients exhibiting the lipid triad of AD requires integrated pharmacotherapy to normalize HDL-C, Triglyceride (TG) and LDL-C levels. Recent studies have focused on optimizing treatment for AD and compare the efficacy and tolerability of combined lipid-altering drug based therapies, however, an optimal pharmacologic approach has not yet been established. The present study was intended to evaluate the restorative efficacy of Extended Release Niacin (ER Niacin) and Fenofibrate as mono and combination therapies , as well as their safety and tolerability in females with obesity-induced AD.

Detailed Description
-----------------
Study Setting: The present study is a single blinded placebo-controlled randomized clinical trial, in which target individuals were obese females (BMI≥30 kg/m2), within the age of 20-60 years, attending the Obesity research and therapy unit of Al-Kindy College of Medicine, University of Baghdad (Baghdad, Iraq), throughout the period from 1st October 2014 to 15th March 2015. Study Protocol: Target individuals with fulfill devoid of exclusion criteria, were further screened and only candidates with conventional diagnosis of AD, as confirmed by a fasting serum TG >150 mg/dl coincide with an HDL-C of less than 50 mg/dl, were considered to be enrolled. Finally, and successive to a comprehensible concise for the expected benefits and side effects on top of the commitment to the entire protocol, eligible candidates settled for participation were provided with a written informed consent. Enrollment: Therapeutic Lifestyle Changes (TLC) Run-in Period: Each and every eligible candidate was enrolled in a four-week TLC run-in (or lead-in) period to exclude responders and to obtain baseline data for non-responders prior to randomization. Randomization and Treatment Allocation: TLC non-responders with persistent AD were randomly allocated to one of the four treatment arms. In order to ensure a periodical balance among all study groups in the course of treatment allocation, permuted-block randomization with a block size of four was implemented and the system produced by this approach was adopted for the sequential random assignment of patients to treatment arms. . Discontinuation of Treatment: Although the absence of published consensus on drug discontinuation in the face of laboratory abnormalities has permitted a spectrum of indefinite decisions, mainly driven by clinical experience, clinical status and tolerability of the patient. For the present study discontinuation of treatment is considered if: Adverse events including flushing, nausea, vomiting, muscle pain, or dizziness turn sever enough to surpass patient's tolerability. Estimated glomerular filtration rate (eGFR) is reduced to ˂ 60ml/min per 1.73 m2 indicating renal insufficiency. Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) increased to>3 Upper Limit of Normal (ULN) with the appearance of nausea, vomiting, fatigue, right upper quadrant pain or tenderness, fever, and/or rash. Serum uric acid exceeds the critical value of 6mg/dl. Assessment of Treatments Responses: Responses to the different treatments arms, in terms of efficacy and safety, are assessed by analyzing clinical and laboratory data collected at each visit over the entire course of the study, including a thorough medical history and previous medication records. Statistical Analysis: All statistical analyses were executed via the statistical package SPSS version 17.0 (SPSS, Inc.). Prior to analysis, Shapiro-Wilk test was used for assessing the normality of distributions for continuous variables, with the data expressed as the mean ± standard error (SE). Analysis of variance (ANOVA) was applied to compare the means of baseline characteristics among different treatments groups. Comprising the influence of the baseline level as a covariate, analysis of covariance (ANCOVA), embracing the least significant difference (LSD) for pair-wise comparison, was applied to assess treatment effects and safety profiles among different arms. Results were evaluated in terms of adjusted end line levels and percent changes from baseline levels. Multivariate Analysis of Covariance (MANCOVA), on the other hand, with further adjustments for relevant covariates was conducted whenever needed. Probability of less than 0.05 was considered statistically significant.

Official Title
-----------------
Efficacy and Safety of Extended Release Niacin-Fenofibrate Combination and Monotherapy for the Treatment of Atherogenic Dyslipidemia in Obese Females

Conditions
-----------------
Atherogenic Dyslipidemia, Obesity Associated Disorder

Intervention / Treatment
-----------------
* Other: Therapeutic Lifestyle Changes
* Other: Placebo
* Drug: Fenofibrate
* Dietary Supplement: Wax Matrix Extended Release Niacin (WMER Niacin)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: BMI≥30 kg/m2. Conventional diagnosis of atherogenic dyslipidemia, confirmed by a fasting serum TG more than150 mg/dl coincide with an HDL-C of less than 50 mg/dl. Exclusion Criteria: The use of any antilipidemic medication. Findings suggestive for renal dysfunction (eGFR˂60ml/min per 1.73 m2). Findings suggestive for hepatic insufficiency (ALT and/or AST˃2ULN). Clinical or laboratory findings suggestive for thyroid dysfunction. Established diagnosis of Diabetes Mellitus. History of gout, hyperuricemia, or on hypouricemic agents. Active peptic ulcer. Pregnancy, or nursing mothers. Alcohol or tobacco consumption.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Non-responders to four-week therapeutic lifestyle changes run-in period, will start to receive an after lunch daily single placebo capsule for eight weeks. | Other: Therapeutic Lifestyle Changes<br>* Four-week therapeutic lifestyle changes run-in period, comprising individualized moderate physical activity and total calories reduction.<br>Other: Placebo<br> <br> |
| Active Comparator: Fenofibrate Monotherapy<br>Non-responders to four-week therapeutic lifestyle changes run-in period, will start to receive an after lunch 200mg daily single dose of fenofibrate (Lipanthyl® 200 mg micronized fenofibrate capsule, Abbott Laboratories Fournier) for eight weeks. | Other: Therapeutic Lifestyle Changes<br>* Four-week therapeutic lifestyle changes run-in period, comprising individualized moderate physical activity and total calories reduction.<br>Drug: Fenofibrate<br> <br> * Other names: Lipanthyl;|
| Active Comparator: WMER Niacin Monotherapy<br>Non-responders to four-week therapeutic lifestyle changes run-in period, will start to receive a night-time 500 mg daily single dose of Wax Matrix Extended Release Niacin (WMER Niacin, ENDUR-ACIN®500mg, Endurance Products Company, Oregon USA) for one week, titrated up to 1000 mg by adding a daily morning-time ENDUR-ACIN®500mg tablet for the next seven weeks. | Other: Therapeutic Lifestyle Changes<br>* Four-week therapeutic lifestyle changes run-in period, comprising individualized moderate physical activity and total calories reduction.<br>Dietary Supplement: Wax Matrix Extended Release Niacin (WMER Niacin)<br> <br> * Other names: ENDUR-ACIN®;|
| Active Comparator: Combination Therapy<br>Non-responders to four-week therapeutic lifestyle changes run-in period, will start to receive an after lunch 200mg daily single dose of fenofibrate for eight weeks, in combination with a night-time 500 mg daily single dose of WMER Niacin for one week, titrated up to 1000mg by adding a daily morning-time ENDUR-ACIN®500mg tablet for the next seven weeks. | Other: Therapeutic Lifestyle Changes<br>* Four-week therapeutic lifestyle changes run-in period, comprising individualized moderate physical activity and total calories reduction.<br>Drug: Fenofibrate<br> <br> * Other names: Lipanthyl;Dietary Supplement: Wax Matrix Extended Release Niacin (WMER Niacin)<br> <br> * Other names: ENDUR-ACIN®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes Serum Triglyceride Levels | Assessments involve the measurement of serum Triglyceride (TG) level. | Treatments effects were assessed by two events, baseline investigations conducted before randomization and end line investigations at the end of the eighth week of treatments. | 
| Changes in Serum Lipoprotein Cholesterol Levels | Assessments involve the measurement of serum Total (TC), High density lipoprotein (HDL-C) and direct Low density lipoprotein (d-LDL-C) cholesterol levels. Serum non HDL-C levels is calculated by subtracting HDL-C from TC. Serum Remnant cholesterol (RC) is calculated by subtracting HDL-C and d-LDL-C from TC. | Treatments effects were assessed by two events, baseline investigations conducted before randomization and end line investigations at the end of the eighth week of treatments. | 
| Changes in Serum Apolipoprotein Levels | Assessments involve the measurement of serum Apolipoprotein A1 (Apo A1) and B (Apo B) levels. | Treatments effects were assessed by two events, baseline investigations conducted before randomization and end line investigations at the end of the eighth week of treatments. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Serum Fasting Glucose Levels. | Assessments involve the measurement of serum fasting glucose levels. | Changes from baseline were assessed at the end eighth week of treatments. | 
| Changes in Estimated Glomerular Filtration Rate (eGFR) | Assessments involve the measurement of serum creatinine which is used to calculate eGFR using the CKD-EPI equation (2009) . | Changes from baseline were assessed at the end of the eighth week of treatments. | 
| Changes in Serum Uric Acid Levels | Assessments involve the measurement of serum uric acid levels | Changes from baseline were assessed at the end of the eighth week of treatments. | 
| Changes in Serum Enzymes Levels | Assessments involve the measurement of serum enzymes including Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Creatine Kinase (CK) levels. | Changes from baseline were assessed at the end of the eighth week of treatments. | 
| Changes in Systolic and Diastolic Blood Pressure | Assessments involve the measurement of systolic and diastolic blood pressure. Patients were allowed to rest for 15 minutes in sitting position, and Walgreens Homedics WGNBPA-540 upper arm blood pressure monitor (Walgreens, China), was used for the measurement of blood pressure. Three consecutive readings were taken at 1 minute interval, and systolic and diastolic blood pressure were calculated as the mean of the last two readings. | Changes from baseline were assessed at the end of the eighth week of treatments. | 
| Adverse Events | Assessments comprise the total number of participants complicating and reporting muscle pain,flushing, nausea, vomiting, and dizziness. As part of the complete safety profile of each arm,other specific reported adverse event are presented in the Adverse Event Module. | Changes from baseline were assessed at the end of the eighth week of treatments. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Extended Release Niacin, Fenofibrate, treatment, Obesity, Atherogenic Dyslipidemia