Clinical Trials Register

Summary
EudraCT Number:	2020-005090-26
Sponsor's Protocol Code Number:	Kleb4V01
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-04-20
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2020-005090-26

A.3

Full title of the trial

Safety and immunogenicity of a Klebsiella pneumoniae tetravalent bioconjugate vaccine (Kleb4V) administered to healthy adults: A FTIH phase I/II randomized and controlled study.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

for german title see below

Sicherheit und Immunogenität eines tetravalenten Biokonjugat-Impfstoffs (Kleb4V) gegen Klebsiella pneumoniae verabreichet an gesunde Erwachsene: Eine randomisierte und kontrollierte Erstanwendungsstudie der Phase I/II.

A.4.1

Sponsor's protocol code number

Kleb4V01

A.5.4

Other Identifiers

Name:

Nuvisan Code

Number:

N-A-PH1-20-029

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	LimmaTech Biologics AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	LimmaTech Biologics AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Nuvisan GmbH
B.5.2	Functional name of contact point	Studieninformation
B.5.3	Address:
B.5.3.1	Street Address	Wegenerstraße 13
B.5.3.2	Town/ city	Neu-Ulm
B.5.3.3	Post code	89231
B.5.3.4	Country	Germany
B.5.4	Telephone number	+497319840222
B.5.5	Fax number	+497319840355
B.5.6	E-mail	studinfo@nuvisan.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Kleb4V
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Kleb4V
D.3.9.1	CAS number	68583-24-4
D.3.9.3	Other descriptive name	Bioconjugate
D.3.9.4	EV Substance Code	SUB14302MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	16 to 64
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	AS03
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AS03
D.3.9.3	Other descriptive name	AS03A
D.3.9.4	EV Substance Code	SUB30838
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	47.45
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	AS03A: Adjuvant System is an oil/water emulsion and contains α-tocopherol (47.45 mg/ml), squalene (42.75 mg/ml) and polysorbate 80 (19.44 mg/ml) in PBS pH 6.8

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Klebsiella pneumoniae (K. pneumoniae), a gram negative Enterobacteriaceae, is an opportunistic pathogen leading to hospital- and community-acquired infections (urinary tract infections, pneumonia and septicaemia).
An effective vaccine could potentially reduce the use of last resort antibiotics by limiting the spread of resistant strains and even prevent infections with pan-resistant isolates, which are not treatable with antibiotics anymore.

E.1.1.1

Medical condition in easily understood language

Vaccine candidate against Klebsiella pneumoniae (Kleb4V)

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10046859
E.1.2	Term	Vaccination
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this Phase I/II study is to obtain first-in-human safety and immunogenicity data following administration of Kleb4V to 55-70 years old adults and identify the preferred formulation of Kleb4V.

E.2.2

Secondary objectives of the trial

Secondary objectives:
- Evaluation of the vaccine induced antibodies at several timepoints following administration of Kleb4V.
- Evaluation of seroconversion (at least 4 fold increase vs. baseline) at 1 month following each vaccination, at 14 days after 1st injection (in Step 2), at V6 pre-2nd dose, and at the end of the study.
- Evaluation of the immunological profile through immunological functional assays confirmed with at least one Klebsiella serotype.

Exploratory objectives:
- Evaluation of the cross-reactivity of the Kleb4V-induced immune-response against selected Klebsiella serotypes not included in Kleb4V vaccine formulations
- Assessment of microbial colonization, including change in Klebsiella spp colonization status at time of first vaccination and at last visit.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Good general health by medical history, laboratory findings and physical examination before receiving vaccination as judged by the investigator (subjects with a minor controlled illness, such as mild controlled hypertension, asthma or COPD, and without fever may be enrolled at the discretion of the investigator)
2. Subject who is willing and able to comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits)
3. Signed written informed consent obtained from the subject
4. For Step 1 Groups 1 and 2 only: Female or male between 18-40 years (inclusive) of age at the time of the first vaccination
5. For Step 1 Groups 3 to 6, and Step 2: Female or male subjects between 55-70 (inclusive) years of age at the time of first vaccination
6. Female subjects of childbearing potential are eligible, as long as they practice adequate contraceptive measures from 2 months before the first vaccination until 1 month after the last vaccination.

E.4

Principal exclusion criteria

1. Health condition that, in the opinion of the investigator, may interfere with optimal participation in the study or place the volunteer at increased risk of adverse events (AEs) Study clinicians, in consultation with the principal investigator, will use clinical judgment on a case-by-case basis to assess safety risks under this criterion
2. Any clinically significant deviation from the normal range in biochemistry or hematology blood tests in the opinion of the investigator
3. Clinically significant abnormalities on physical examination
4. Suspected or known hypersensitivity (including allergy) to any of the vaccine components or to medicinal products or medical equipment whose use is foreseen in this study
5. History of allergy to any vaccine
6. Clinical conditions representing a contraindication to intramuscular vaccination and blood draws (e.g. coagulation disorder)
7. Acute or chronic, clinically significant cardiovascular, pulmonary, hepatic or renal abnormality diseases and/or insufficiency as determined by physical examination or laboratory tests. In particular: unstable current or history of coronary artery disease or cardiac insufficiency, uncontrolled hypertension, clinically significant history of myocardial infarction, atrial fibrillation, uncontrolled or clinically significant type 2 diabetes, current or history of rheumatoid arthritis or temporal arteritis, current acute or chronic active pulmonary diseases
Note: Subjects may be on chronic or as needed medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition
8. Known or suspected impairment of immunological function, documented Human Immunodeficiency Virus (HIV) infection, asplenia/splenectomy, or history of autoimmune disease or lymphoprolipherative disorder
9. Positive blood test for HBsAg, HCV, HIV-1/2
10. Positive test for SARS-CoV-2
11. History of systemic administration of immunosuppressive drugs, i.e. corticosteroids, (PO/IV/IM) within the last 4 weeks prior to 1st vaccination or for more than 14 consecutive days within 3 months prior to 1st vaccination until the last blood sampling visit (i.e prednisone or equivalent ≥20 mg/day). Inhaled and topical steroids are allowed.
12. Administration of antineoplastic and immune-modulating agents or chemotherapy within 90 days prior to informed consent
13. Planned administration of a vaccine not foreseen by the study protocol within 4 weeks prior to 1st vaccination and 4 weeks after last vaccination. Vaccination against seasonal influenza virus (or CoVID vaccine if on the market) is allowed outside of +/- 7 days from each vaccination
14. Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational interventional vaccine/product (pharmaceutical product)
15. Body Mass Index (BMI) <19 and >30
16. History of any chronic or progressive disease that according to judgment of the investigator could interfere with the study outcomes or pose a threat to the participant's health
17. Received an investigational or non-registered product (medicinal drug or vaccine), other than the study vaccine within 3 months prior to 1st administration of study vaccine, or planned use during the study period
18. Administration of immunoglobulin and/or any blood products within the three months preceding the first dose of study vaccine
19. Blood donation of at least 500 mL blood draw within 3 months preceding injection or planned during the study period as reported by subject
20. Use of any antibiotic therapy within 1 week preceding each injection
21. Subjects with an elective surgical intervention, planned during the study period until 30 days after 2nd vaccination
22. Females lactating, or pregnancy or intention to become pregnant as reported by subject
23. Current and/or history of chronic alcohol consumption and/or drug abuse
24. History of immune-mediated disease (see Table of pIMDs in Annex).
25. Heavy smokers (> 20 cigarettes per day)

E.5 End points

E.5.1

Primary end point(s)

Safety and Immunogenicity

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety
- Occurrence, severity and relationship of solicited local and general AEs during 7 days following each vaccination (i.e. day of vaccination and the 6 subsequent days)
- Occurrence, severity and relationship of unsolicited AEs during 28 days following each vaccination (i.e. day of injection and the 27 subsequent days)
- Occurrence, severity and relationship of medically relevant AEs, AESIs and SAEs throughout the study duration.

Immunogenicity
- Evaluation of geometric mean titers (GMTs) for serum IgG against the four K. pneumoniae O-serotypes included in Kleb4V, between baseline and post- vaccination samples collected at V8 (i.e. 28 days after the second injection).

E.5.2

Secondary end point(s)

-Evaluation of geometric mean titers (GMTs) for serum IgG against the four K. pneumoniae O-serotypes included in Kleb4V on samples collected at V4, V5, V6 and at the last study visit (V9) vs. baseline.
-Evaluation of fold-increases between baseline and post- vaccination samples of serum IgG against the four K. pneumoniae O-serotypes included in Kleb4V, collected at V4, V5, V6, V8, and V9.
-Percentage of subjects achieving at least a four-fold rise in anti-O antigens K. pneumoniae antibody concentration at V5 and V8 (i.e. 28 days after each injection), at V4 (i.e. 14 days after 1st injection (as applicable in Step 2)), at V6 pre-2nd dose and at V9 at the end of the study, compared to baseline.
-Evaluation of antibody functionality (i.e. by opsonic titer, avidity or serum bactericidal assay) in post vs. pre-vaccination samples and between arms vs placebo.

E.5.2.1

Timepoint(s) of evaluation of this end point

-Evaluation of geometric mean titers (GMTs) for serum IgG against the four K. pneumoniae O-serotypes included in Kleb4V on samples collected at V4, V5, V6 and V9 vs. baseline.
-Evaluation of fold-increases between baseline and post- vaccination samples of serum IgG against the four K. pneumoniae O-serotypes included in Kleb4V, collected at V4, V5, V6, V8, and V9.
-Percentage of subjects achieving at least a four-fold rise in anti-O antigens K. pneumoniae antibody concentration at V5 and V8, at V4, at V6 pre-2nd dose and at V9, compared to baseline.
-Evaluation of antibody functionality (i.e. by opsonic titer, avidity or serum bactericidal assay) in post vs. pre-vaccination samples and between arms vs placebo.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

116

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

166

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-06-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-01-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-09-26

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