Microdose and First-In-Human (FIH) Study of Recombinant Human Placental Alkaline Phosphatase (hRESCAP)

Healthy Clinical Trial

Official title:

A Single Dose Study to Assess the Peak Plasma Concentration of a Microdose of Recombinant Human Placental Alkaline Phosphatase (hRESCAP, Part 1) Followed by a Single Ascending Dose, FIH Study to Assess Safety and Tolerability of hRESCAP (Part 2).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01889147
• Other study ID #: CHDR1220
• Status: Completed
• Phase: Phase 0
• First received: June 18, 2013
• Last updated: October 23, 2013
• Start date: June 2013
• Est. completion date: October 2013

Study information

• Verified date: October 2013
• Source: TNO
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

In the present study human recombinant placental alkaline phosphatase (hRESCAP) will be investigated. Alkaline Phosphatase is naturally present in the body and reported to use lipopolysaccharde (LPS, bacterial endotoxins) and extracellular nucleotides leaking from damaged and ischemic cells as physiological substrates. The LPS-substrate prevalence makes alkaline phosphatase an interesting novel therapeutic agent in the treatment of LPS-mediated diseases. A bovine homologue of this protein (bovine intestinal alkaline phosphatase, BIAP) has previously been investigated for treatment of acute inflammatory responses such as sepsis, and was shown to be safe in humans. hRESCAP, which will be investigated in the current study, is expected to have a longer half-life in humans than the previously investigated BIAP, due to the fact that it is more sialylated. The possibility to increase the t1/2 to days instead of minutes enables treatment of chronic diseases.

Description:

In the current study the peak plasma concentration (pharmacokinetics/elimination) of [14C]-labelled hRESCAP in healthy volunteers will be investigated at increasing single doses (up to anticipated therapeutic dose), with a microdose (≤30 nmol) as a safe starting dose.

• Part 1: To assess the peak plasma concentration of a single microdose (≤30 nmol) of a recombinant human protein (hRESCAP), administered intravenously, as a suitable technique to predict the pharmacokinetics in humans at pharmacologically relevant doses;

• Part 2: To determine the safety and tolerability of single dose of hRESCAP up to 5300 µg in healthy male volunteers administered intravenously;

• To determine the peak plasma concentration of hRESCAP in healthy male volunteers within a pharmacologically relevant dose-range and compare this with BIAP pharmacokinetics with emphasis on half-life (t1/2).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4
• Est. completion date: October 2013
• Est. primary completion date: July 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 45 Years

Eligibility

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, over the counter medications, vitamin, herbal and dietary supplements 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, food (ingredients) or device 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 is not allowed for subjects participating in part 2.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Healthy

Intervention

Biological:
• hRESCAP
one acute bolus administration of different dosages of hRESCAP (microdose, part 1; and FIH: low dose, 414 µg; medium dose, 2480 µg; high dose, 5300 µg; part 2)
• Placebo

Locations

Country	Name	City	State
Netherlands	Centre for Human Drug Research	Leiden	South-Holland

Sponsors (2)

Lead Sponsor	Collaborator
TNO	Alloksys Life Sciences B.V.

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluate the peak plasma concentration of hRESCAP after microdose administration of hRESCAP	After administration of hRESCAP intravenously, blood will be withdrawn of the subjects frequently for in total 35 days (five times the anticipated half-life period of one week).	35 days	Yes
Secondary	In the ascending dose study increased dosages of of hRESCAP will be supplied till finally the therapeutic dose.	In three subjects a low, medium and high dose of hRESCAP will be administered and a control saline administration in one subject. The peak plasma concentration of hRESCAP response of different dosages will be useful for treatment evaluation. The administration of the different dosages supplied is one week apart for safety reasons.	Two weeks (based upon time phrame of micodose section of the study)	Yes