Study Assessing Safety, Immunogenicity and LDLc -Lowering Activity of 2 PCSK9 Targeting AFFITOPE Vaccines in Healthy Subjects

Study Overview
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Brief Summary
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Study AFF012 is a single blind, single-center, randomized, placebo-controlled, parallel group, phase I clinical trial of repeated administration by subcutaneous injection of a single dose of one of two different proprotein convertase subtilisin/kexin type 9 targeting AFFITOPE® vaccines or Placebo. This study will assess Safety, Immunogenicity and low density lipoprotein cholesterol-lowering activity of the two vaccines. 72 healthy subjects are divided into three test groups (2 treatment groups, 1 placebo group), each consisting of 24 subjects. The subjects are randomized to receive either of two AFFITOPEs® (AT04A or AT06A, adsorbed to 1 mg aluminium oxyhydroxide) or placebo (1 mg aluminium oxyhydroxide). The study consists of 3 parts, part A, encompassing Visit 1 to Visit 8, covering 3 priming immunizations at a dose of 15μg at days 0, 28 and 56 and the immediate observation period extending to day 140; the prolonged observation period: part B, encompassing Visit 9 and Visit 10 at days 273 and 365; and part C consisting of 7 visits (V11 to V17). Study participants having received 3 priming vaccinations and having completed part B will receive in part C one boost immunization at a dose of 75μg, which will be applied one year after the 3rd immunization (day 420). Probands will proceed directly from part A to part B and to part C. Continuation of parts B and C will be considered based on the part A results, primarily the immunological results. The following scenarios apply (provided that there is no safety issue). None of the two treatment groups exhibits a vaccine-specific antibody response over the placebo group at Visit 8 - this will lead to termination of the trial. One of the two groups fails to exhibit a vaccine-specific antibody response over the placebo group at Visit 8 - this will lead to its discontinuation; the other treatment group and the placebo group will be continued.

Official Title
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A Single-blind Phase 1 Study Assessing the Safety, Immunogenicity and Low Density Lipoprotein Cholesterol (LDLc)-Lowering Activity of 2 Different Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Targeting AFFITOPE® Vaccines in Healthy Subjects

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Biological: AFFITOPE® AT04A+adjuvant
* Biological: AFFITOPE® AT06A+adjuvant
* Biological: Adjuvant without active component


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects ≥ 18 years of age at time of study entry. Fasting LDLc at screening. Fasting triglycerides at screening. Body weight > 50 kg and a body mass index (BMI) between 19 and 35. Exclusion Criteria: Treatment/change in treatment with medications known to influence HDLc, LDLc and total cholesterol concentrations Planned life-style changes during the study period like increasing aerobic exercise activity, attempting to lose body weight or changing the smoking status. History of autoimmune diseases. History of malignancy Active or passive vaccination Blood donation History of severe hypersensitivity reactions and anaphylaxis. History of allergic bronchial asthma. Acquired or hereditary immunodeficiency. Prior and/or current treatment with immune modulating drugs: Subject has taken prescription lipid-regulating drugs Treatment prior to screening with the following drugs: vitamin A derivatives and retinol derivatives for dermatologic treatment or any other drug known to influence cholesterol Levels Infection with the human immunodeficiency Virus,Hepatitis B (HBsAg) or Hepatitis C.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AFFITOPE® AT04A+adjuvant<br>3 injections of 15µg AFFITOPE® AT04A+adjuvant once every 4 weeks and 1 boost immunization at a dose of 75μg, which will be applied one year after the 3rd immunization | Biological: AFFITOPE® AT04A+adjuvant<br>* subcutaneous injection<br>|
| Experimental: AFFITOPE® AT06A+adjuvant<br>3 injections of 15µg AFFITOPE® AT06A+adjuvant once every 4 weeks and 1 boost immunization at a dose of 75μg, which will be applied one year after the 3rd immunization | Biological: AFFITOPE® AT06A+adjuvant<br>* subcutaneous injection<br>|
| Placebo Comparator: Adjuvant without active component<br>3 injections of Placebo once every 4 weeks and 1 boost immunization which will be applied one year after the 3rd immunization | Biological: Adjuvant without active component<br>* subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurence of any Serious Adverse Event (SAE) | Evaluation of SAE being unlikely, possibly, probably or definitely related to the study vaccines Occurence of any Grade 3 or higher adverse Event (AE) Occurence of solicited local AEs Occurence of solicited systemic AEs Occurence of unsolicited non-serious AEs | 21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunological activity of AFFITOPE® AT04A: Titer of vaccination-induced antibodies | Titer of vaccination-induced antibodies directed towards peptide components of the vaccine, the carrier, and the target proprotein convertase subtilisin/kexin type 9 | 21 months | 
| Immunological activity of AFFITOPE® AT06A: Titer of vaccination-induced antibodies | Titer of vaccination-induced antibodies directed towards peptide components of the vaccine, the carrier, and the target proprotein convertase subtilisin/kexin type 9 | 21 months | 
| Mean Levels of Low Density Lipoprotein Cholesterol (LDLc) | Change from baseline | 21 months | 
| Mean Levels of High Density Lipoprotein Cholesterol (HDLc) | Change from baseline | 21 months | 
| Mean Levels of Very Low Density Lipoprotein (VLDL) | Change from baseline | 21 months | 
| Mean Levels of Total Cholesterol (TC) | Change from baseline | 21 months | 
| Mean Levels of Triglycerides (TG) | Change from baseline | 21 months | 
| Mean Levels of PCSK9 | Change from baseline | 21 months | 
| Correlation analysis: Relating the strength of antibody responses to Lipid lowering effects | Relating the strength of antibody responses to Lipid lowering effects | 21 months |