Part 1:- To assess the PK of a single iv microdose (
ID
Source
Brief title
Condition
- Autoimmune disorders
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability / Safety endpoint
- Assessment of adverse events, local tolerability, vital signs, clinical
chemistry and haematology parameters.
Pharmacokinetic endpoints
- Assessment of PK after microdose administration of 53 µg [14C]-hRESCAP;
- Determination of the half-life of [14C]-hRESCAP within pharmacological
relevant dose-range (414-5300 µg).
Pharmacodynamic endpoints
- Assessment of the total alkaline phosphatase activity by standard assay;
- Determination of placental alkaline phosphatase activity with an assay
specific for placental alkaline phosphatase.
Secondary outcome
N/A
Background summary
Alkaline phosphatase (AP) is a common endogenous enzyme, which is present in
many cells and/or organs in the human body (e.g. intestine, placenta, liver,
bone, kidney and neutrophilic granulocytes). Although the role of this enzyme
is not fully elucidated, there is growing evidence that AP plays a significant
role in host defence and innate immunity, particularly against inflammatory
reactions due to release of endotoxin and other phosphorylated pro-inflammatory
substrates (e.g. extracellular nucleotides).
Various forms of AP exist. Bovine Intestinal Alkaline Phosphatase (BIAP) was
developed with the intention to prevent acute ischemia-reperfusion mediated
inflammation. From all studies in animal species and humans it was concluded
that bovine AP is well tolerated in species that are tolerant for this bovine
protein. For chronic inflammatory disease Alloksys developed a recombinant
placental alkaline phosphatase with more favorable plasma kinetics (e.g. a
longer half-life), compatible to routine use therapeutic applications.
Therapeutic targets are patients suffering from disease like Rheumatoid
Arthritis (RA), asthma, and Multiple Sclerosis (MS) that are either resistant
to classic disease-modifying antirheumatic drugs (DMARDS) pharmaceuticals like
methotrexate (MTX) or those that are tolerant to biological TNF-α blocker
products. Due to its different mode of action (MOA) hRESCAP is considered to be
an alternative to these TNF-α blockers. Application of hRESCAP as single
therapeutic entity is foreseen, albeit that due to its different MOA also
combination treatment with classic pharmaceuticals or TNF-α blockers will be
enabled as well. It is understood that this hRESCAP may be applied as well in
acute settings.
Study objective
Part 1:
- To assess the PK of a single iv microdose (<=30 nmol) of recombinant human
placental alkaline phosphatase (hRESCAP);
- To assess if microdosing is a suitable technique to predict the PK of
recombinant proteins using hRESCAP as model in humans at pharmacologically
relevant doses (in combination with the results obtained in part 2);
Part 2:
- To determine the safety and tolerability of single iv dose of hRESCAP in
doses up to 5300 µg in healthy volunteers;
- To determine the pharmacokinetics and pharmacodynamics of ascending iv doses
of hRESCAP in healthy volunteers within a pharmacologically relevant dose-range
and compare this with BIAP pharmacokinetics with emphasis on half-life (t1/2).
Study design
Part 1: An open label study of single doses of hRESCAP administered
intravenously to healthy male volunteers.
Part 2: A randomized, double-blind, placebo-controlled, parallel,
first-in-human study of single ascending doses of hRESCAP administered
intravenously to healthy male volunteers.
Intervention
Part 1
Group 1: 53 µg 14C-hRESCAP
Part 2
Group 2: 414 µg 14C-hRESCAP / matching placebo
Group 3: 2480 µg 14C-hRESCAP / matching placebo
Group 4: 5300 µg 14C-hRESCAP / matching placebo
Study burden and risks
Of investigational products that have not been administered to humans before
such as hRESCAP, not all adverse events are known and unexpected adverse events
could occur such as hypersensitivity reactions.
Zernikedreef 8
Leiden 2333 CL
NL
Zernikedreef 8
Leiden 2333 CL
NL
Listed location countries
Age
Inclusion criteria
1. Healthy male subjects, 18 - 45 years of age, inclusive. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis;
2. Body mass index (BMI) between 18 and 30 kg/m2, inclusive;
3. Ability to communicate well with the investigator in the Dutch language;
4. Able to participate and willing to give written informed consent and to comply with the study restrictions;
5. Venous access sufficient to allow blood sampling as per protocol.
Exclusion criteria
1. Any clinically significant abnormality as determined by medical history taking and physical examinations obtained during the screening visit that in the opinion of the investigator would interfere with the study objectives or compromise subject safety;
2. History of a surgical event that may significantly affect the study outcome;
3. History of allergy or other inflammatory indications;
4. History of asthma or other inflammatory disease;
5. Use of prescription medications within 21 days prior to study drug administrations, or less than 5 half-lives, whichever is longer, and during the course of the study.
6. Alkaline Phosphatase levels in plasma of < 30 IU/L or > 115 IU/L;
7. Clinically relevant abnormal laboratory results, ECG, vital signs, or physical findings at screening that in the opinion of the investigator would interfere with the study objectives or compromise subject safety;
8. Participation in an investigational drug study within 3 months prior to screening or more than 4 times in the past year;
9. Any psychological conditions which, in the opinion of the investigator, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol;
10. History of alcohol or illicit drug abuse (alcohol abuse defined as alcohol consumption > 28 units/week);
11. Reported unexplained weight loss or weight gain of > 2 kg in the month prior to screening;
12. Positive test results for Hepatitis B, Hepatitis C or HIV;
13. Donation of blood within 3 months prior to screening or donation of plasma within 14 days prior to screening;
14. Not having a general practitioner;
15. Not willing to accept information transfer which concerns participation in the study, or information regarding health, like laboratory results, findings at anamnesis or physical examination and eventual adverse events to and from his general practitioner;
16. Not willing to give permission to have the general practitioner to be notified upon participation in this study;
17. Prior participation in part 1 for subjects participating in part 2 of the study;
18. Not willing to use effective (double barrier) contraception until at least 3 months after dose administration.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001814-13-NL |
| CCMO | NL44653.056.13 |