Brazilian Cardioprotective Diet, Phytosterols and Krill Oil in Patients With Familial Hypercholesterolemia

Study Overview
=================
Brief Summary
-----------------
The main objective of this pilot study is to evaluate the effects of the Brazilian Cardioprotective Diet (DICA Br) supplemented or not with phytosterols and/or krill oil in patients with a probable or definitive diagnosis of familial hypercholesterolemia (FH) identified by the Dutch Lipid Clinic Network (Dutch MEDPED) criteria. In addition, the following will be considered secondary objectives: to perform participants´ complete sequencing of the exome; to evaluate the effects of the interventions on lipid profile; to identify subclasses of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol; to perform untargeted lipidomic analyses; to evaluate the frequency of mild, moderate and severe adverse events according to study groups; and to evaluate both implementation components and adherence rates to the protocol, aiming to design a larger randomized trial. In this pilot study, between 48 and 76 individuals will be randomly enrolled into four groups: 1) DICA Br adapted to FH (DICA-HF) + phytosterol placebo + krill oil placebo (control group); 2) DICA-HF + 2g/day of phytosterol + krill oil placebo; 3) DICA-HF + phytosterol placebo + 2g/day of krill oil; and 4) DICA-HF + 2g/day of phytosterol + 2g/day of krill oil. Primary outcomes will be LDL-cholesterol for groups phytosterol vs. placebo and lipoprotein(a) for groups krill oil vs. placebo after 120 days of follow up. World Health Organization Universal Trial Number (WHO-UTN): U1111-1296-7102

Detailed Description
-----------------
DICA-HF pilot study is a superiority, factorial, and in parallel randomized placebo-controlled (double-dummy) clinical trial. The randomization will be in blocks of varying sizes stratified by research center, and the allocation ratio will be 1:1:1:1. Participants will come from at least 9 center sites in different Brazilian geographic regions.

Official Title
-----------------
Effect of the Adapted Brazilian Cardioprotective Diet Supplemented With Phytosterols and/or Krill Oil in Patients With Familial Hypercholesterolemia: DICA-HF Pilot Study

Conditions
-----------------
Familial Hypercholesterolemia

Intervention / Treatment
-----------------
* Dietary Supplement: phytosterol
* Dietary Supplement: krill oil
* Other: Placebo phytosterol
* Other: Placebo krill oil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult participants (age ≥20 years); Definitive (certainty) or probable diagnosis of FH by the Dutch MEDPED criteria; Using one of the following treatment regimens for ≥ 6 weeks: simvastatin 40 mg; lovastatin 40 mg; pravastatin 80 mg; atorvastatin 20 mg; rosuvastatin 10 mg; pitavastatin 4 mg; fluvastatin 80 mg; atorvastatin 40 - 80 mg; rosuvastatin 20 - 40 mg; atorvastatin 40 - 80 mg + ezetimibe 10mg; rosuvastatin 20 - 40 mg + ezetimibe 10mg; or simvastatin 40mg + ezetimibe 10mg. Exclusion Criteria: Possible diagnosis of FH according to the Dutch MEDPED criteria; Fasting triglycerides ≥ 500mg/dL; Diagnosis of hypercholesterolemia due to a secondary cause (hypothyroidism, nephrotic syndrome, etc.); Food allergies (food, dyes, preservatives); Contraindication to the use of phytosterols (for example: diagnosis of sitosterolemia); HIV positive in treatment/AIDS; Chronic inflammatory diseases; Liver disease or chronic kidney disease on dialysis; Cancer under treatment or life expectancy < 6 months; Episode of acute coronary syndrome in the last 60 days; Chemical dependency/alcoholism; Chronic use of anti-inflammatory, anticonvulsant and immunosuppressive drugs; Use of PCSK9 inhibitors (alirocumab and evolocumab); Pregnancy or lactation; Wheelchair users unable to undergo anthropometric assessment; Body mass index ≥40kg/m²; Use of dietary supplements that may interfere with the outcomes of interest; Participation in other randomized clinical trials; Refusal to participate in the study.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: DICA-HF + placebo<br>Participants allocated into this arm (n= 24) will receive the DICA Br adapted to FH (DICA-HF) plus placebo of both phytosterol and krill oil during 120 days. | Other: Placebo phytosterol<br>* Placebo of phytosterol, in the same quantity of the active phytosterol<br>Other: Placebo krill oil<br>* Placebo of krill oil, in the same quantity of the active krill oil<br>|
| Experimental: DICA-HF + phytosterol<br>Participants allocated into this arm (n= 24) will receive the DICA Br adapted to FH (DICA-HF) plus 2g/day of phytosterol and placebo of the krill oil during 120 days. | Dietary Supplement: phytosterol<br>* 2g/day will be provided to the participants, aiming to guarantee a minimum of 800mg/day of free phytosterols.<br>Other: Placebo krill oil<br>* Placebo of krill oil, in the same quantity of the active krill oil<br>|
| Experimental: DICA-HF + krill oil<br>Participants allocated into this arm (n= 24) will receive the DICA Br adapted to FH (DICA-HF) plus 2g/day of krill oil and placebo of phytosterol during 120 days. | Dietary Supplement: krill oil<br>* 2g/day will be provided to the participants, aiming to guarantee a minimum of 400mg/day of eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids.<br>Other: Placebo phytosterol<br>* Placebo of phytosterol, in the same quantity of the active phytosterol<br>|
| Experimental: DICA-HF + phytosterol + krill oil<br>Participants allocated into this arm (n= 24) will receive the DICA Br adapted to FH (DICA-HF) plus 2g/day of phytosterol and 2g/day of krill oil during 120 days. | Dietary Supplement: phytosterol<br>* 2g/day will be provided to the participants, aiming to guarantee a minimum of 800mg/day of free phytosterols.<br>Dietary Supplement: krill oil<br>* 2g/day will be provided to the participants, aiming to guarantee a minimum of 400mg/day of eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LDL-c | Low-density lipoprotein cholesterol, in mg/dL | 120 days | 
| Lp(a) | Lipoprotein(a), in mg/dL | 120 days | 
| Adherence | Adherence to treatment, evaluated by: attendance at consultations (at least 3 of the 4 planned study visits); plasma concentrations of phytosterols and erythrocyte levels of EPA/DHA fatty acids (identified by the difference between the last and the first study visits); and counting the consumed products under investigation (consumption of at least 80% of the capsules provided to the participants, regardless of the allocation group). | 120 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TC | Total cholesterol, in mg/dL | 120 days | 
| HDL-c | High density lipoprotein cholesterol, in mg/dL | 120 days | 
| TG | Fasting triglycerides, in mg/dL | 120 days | 
| VLDL | Very low-density lipoprotein cholesterol, in mg/dL | 120 days | 
| NHDL | Non-HDL cholesterol, in mg/dL, calculated according to the mathematical formula: CT - HDL-c | 120 days | 
| CI I | Castelli Index I, in mg/dL, calculated according to the mathematical formula: CT/HDL-c | 120 days | 
| CI II | Castelli Index II, in mg/dL, calculated according to the mathematical formula: LDL-c/HDL-c | 120 days | 
| TG/HDL-c | TG/HDL-c ratio, in mg/dL, calculated according to the mathematical formula: TG/HDL-c | 120 days | 
| AI | Atherogenic index, in mg/dL, calculated according to the mathematical formula: NHDL/HDL-c | 120 days | 
| ox-LDL | Oxidized LDL, in µg/mL | 120 days | 
| AE | Adverse events (mild, moderate and severe), registered as percentage per study group | 120 days | 
| Implementation | Implementation components, measured by: on-time recruitment rates; choice and adjustments of remote platform/media for center sites training; measures of participants´ engagement to interventions; and rates of loss to follow-up. | 120 days |