Clinical trial NCT02508896: Study Assessing Safety, Immunogenicity and LDLc -Lowering Activity of 2 PCSK9 Targeting AFFITOPE Vaccines in Healthy Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypercholesterolemia
Lead sponsor: Affiris AG
Sponsor class: INDUSTRY
Collaborators: name: Medical University of Vienna
First posted: 2015-07-27
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Subjects ≥ 18 years of age at time of study entry.
2. Fasting LDLc at screening.
3. Fasting triglycerides at screening.
4. Body weight \> 50 kg and a body mass index (BMI) between 19 and 35.

Exclusion Criteria:

1. Treatment/change in treatment with medications known to influence HDLc, LDLc and total cholesterol concentrations
2. Planned life-style changes during the study period like increasing aerobic exercise activity, attempting to lose body weight or changing the smoking status.
3. History of autoimmune diseases.
4. History of malignancy
5. Active or passive vaccination
6. Blood donation
7. History of severe hypersensitivity reactions and anaphylaxis.
8. History of allergic bronchial asthma.
9. Acquired or hereditary immunodeficiency.
10. Prior and/or current treatment with immune modulating drugs:
11. Subject has taken prescription lipid-regulating drugs
12. 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
13. Infection with the human immunodeficiency Virus,Hepatitis B (HBsAg) or Hepatitis C.

Primary outcomes:
measure: Occurence of any Serious Adverse Event (SAE)
timeFrame: 21 months
Secondary outcomes:
measure: Immunological activity of AFFITOPE® AT04A: Titer of vaccination-induced antibodies
timeFrame: 21 months
measure: Immunological activity of AFFITOPE® AT06A: Titer of vaccination-induced antibodies
timeFrame: 21 months
measure: Mean Levels of Low Density Lipoprotein Cholesterol (LDLc)
timeFrame: 21 months
measure: Mean Levels of High Density Lipoprotein Cholesterol (HDLc)
timeFrame: 21 months
measure: Mean Levels of Very Low Density Lipoprotein (VLDL)
timeFrame: 21 months
measure: Mean Levels of Total Cholesterol (TC)
timeFrame: 21 months
measure: Mean Levels of Triglycerides (TG)
timeFrame: 21 months
measure: Mean Levels of PCSK9
timeFrame: 21 months
measure: Correlation analysis: Relating the strength of antibody responses to Lipid lowering effects
timeFrame: 21 months
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
Study officials:
affiliation: Medical University of Vienna
name: Markus Zeitlinger, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zeitlinger M, Bauer M, Reindl-Schwaighofer R, Stoekenbroek RM, Lambert G, Berger-Sieczkowski E, Lagler H, Oesterreicher Z, Wulkersdorfer B, Luhrs P, Galabova G, Schwenke C, Mader RM, Medori R, Landlinger C, Kutzelnigg A, Staffler G. A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9. Eur J Clin Pharmacol. 2021 Oct;77(10):1473-1484. doi: 10.1007/s00228-021-03149-2. Epub 2021 May 10.