Study Assessing Safety, Immunogenicity and LDLc -Lowering Activity of 2 PCSK9 Targeting AFFITOPE Vaccines in Healthy Subjects (AFF012)

• ClinicalTrials.gov Identifier: NCT02508896
• Recruitment Status: Completed
• First Posted: July 27, 2015
• Last Update Posted: October 20, 2017
• Sponsor: Affiris AG
• Collaborator: Medical University of Vienna
• Information provided by (Responsible Party): Affiris AG

Tracking Information

• First Submitted Date: July 24, 2015
• First Posted Date: July 27, 2015
• Last Update Posted Date: October 20, 2017
• Study Start Date: July 2015
• Actual Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 9, 2016)

Occurence of any Serious Adverse Event (SAE) [ Time Frame: 21 months ]

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

Original Primary Outcome Measures (submitted: July 24, 2015)

Occurence of any Serious Adverse Event (SAE) [ Time Frame: 12 months ]

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

Current Secondary Outcome Measures (submitted: September 9, 2016)

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

Original Secondary Outcome Measures (submitted: July 24, 2015)

• Immunological activity of AFFITOPE® AT04A: Titer of vaccination-induced antibodies [ Time Frame: 12 months ]
  Titer of vaccination-induced antibodies directed towards peptide components of the vaccine, the carrier, and the target proprotein convertase subtilisin/kexin type 9
• Immunological activity of AFFITOPE® AT06A: Titer of vaccination-induced antibodies [ Time Frame: 12 months ]
  Titer of vaccination-induced antibodies directed towards peptide components of the vaccine, the carrier, and the target proprotein convertase subtilisin/kexin type 9
• Mean Levels of Low Density Lipoprotein Cholesterol (LDLc) [ Time Frame: 12 months ]
  Change from baseline
• Mean Levels of High Density Lipoprotein Cholesterol (HDLc) [ Time Frame: 12 months ]
  Change from baseline
• Mean Levels of Very Low Density Lipoprotein (VLDL) [ Time Frame: 12 months ]
  Change from baseline
• Mean Levels of Total Cholesterol (TC) [ Time Frame: 12 months ]
  Change from baseline
• Mean Levels of Triglycerides (TG) [ Time Frame: 12 months ]
  Change from baseline
• Mean Levels of PCSK9 [ Time Frame: 12 months ]
  Change from baseline
• Correlation analysis: Relating the strength of antibody responses to Lipid lowering effects [ Time Frame: 12 months ]
  Relating the strength of antibody responses to Lipid lowering effects

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: Hypercholesterolemia

Intervention

• Biological: AFFITOPE® AT04A+adjuvant
  subcutaneous injection
• Biological: AFFITOPE® AT06A+adjuvant
  subcutaneous injection
• Biological: Adjuvant without active component
  subcutaneous injection

Study Arms

• Experimental: AFFITOPE® AT04A+adjuvant
  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
  Intervention: Biological: AFFITOPE® AT04A+adjuvant
• Experimental: AFFITOPE® AT06A+adjuvant
  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
  Intervention: Biological: AFFITOPE® AT06A+adjuvant
• Placebo Comparator: Adjuvant without active component
  3 injections of Placebo once every 4 weeks and 1 boost immunization which will be applied one year after the 3rd immunization
  Intervention: Biological: Adjuvant without active component

• Publications *: Zeitlinger M, Bauer M, Reindl-Schwaighofer R, Stoekenbroek RM, Lambert G, Berger-Sieczkowski E, Lagler H, Oesterreicher Z, Wulkersdorfer B, Lührs 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 May 10. doi: 10.1007/s00228-021-03149-2. [Epub ahead of print]

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 24, 2015): 72
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 31, 2017
• Actual Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria

Administrative Information

• NCT Number: NCT02508896
• Other Study ID Numbers: AFFiRiS 012; 2015-001719-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Affiris AG
• Study Sponsor: Affiris AG
• Collaborators: Medical University of Vienna

Investigators

• Principal Investigator: Markus Zeitlinger, MD; Medical University of Vienna

• PRS Account: Affiris AG
• Verification Date: October 2017