Safety and Dose-finding Study of DC-TAB in Healthy Subjects

A Phase I, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and T-cell Tolerizing Effect of DC-TAB in Healthy Volunteers

The purpose of this study is to determine safety and appropriate dose of DC-TAB for selective immune tolerance induction in humans.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Biological: recombinant human alpha B-crystallin; Other: placebo comparator

Detailed Description

This study is a double-blind, randomized, placebo-controlled, dose-escalation study of DC-TAB in healthy human volunteers. DC-TAB is a solution of the small heat-shock protein alpha B-crystallin for intravenous injection, designed to induce selective immunological tolerance as a treatment for multiple sclerosis. In this first-in-man study, DC-TAB is administered to healthy subjects in varying doses and for a varying number of times, after which safety and tolerability is evaluated, as well as the impact of the treatment on antigen-specific responses by peripheral blood T cells and serum antibodies. Blood samples are additionally collected to measure serum concentrations of DC-TAB, and to determine the rate of clearance from the circulation. The study is double blind and placebo-controlled to strengthen the significance especially of immunological evaluations.

The study consists of two parts. In Part 1, subjects receive a single dose of DC-TAB or placebo whereas in Part 2, (different) subjects receive DC-TAB or placebo on 3 consecutive days. In Part 1, four groups of subjects (n=10) are studied in a single dose, dose-escalation design. Each group of subjects are randomized to receive either DC-TAB (n=8) or placebo (n=2) once. In Part 2, three groups of subjects (n=12) are studied in a multiple dose, dose-escalation design. Each group of subjects are randomized to receive either DC-TAB (n=9) or placebo (n=3) once daily on 3 consecutive days. The next higher dose group in each part of the study only starts once safety data up to 4 days for Part 1, up to 8 days for Part 2 of the previous dose group have been reviewed and have raised no safety concerns. Part 2 is started once all safety data of Part 1 have been reviewed. Immunological effects of the treatments are evaluated over a period of 28 days.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584CJ
    • Kendle International

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Caucasian
• Signed the written informed consent form before first screening procedure
• Age ≥ 18 years and ≤ 55 years
• In general good health in the opinion of the investigator
• BMI between 20.0 and 28.0 kg/m2
• Use of adequate and stable contraception for 3 months prior to study initiation, during the course of the study and 30 days thereafter. Sexually active males must use a condom. Sexually active females must use double-barrier contraception or hormonal contraceptive (oral, transdermal, vaginal ring, implants), or must have undergone clinically documented total hysterectomy and/or oophorectomy, surgical sterilization or be postmenopausal defined by amenorrhea for at least 12 months and confirmed with a FSH higher than 40 IU/mL.
• If subjects claim abstinence as their method of contraception, they must be willing to agree to use condoms if they become sexually active from 14 days prior to the first dose of the study drug through 90 days beyond the conclusion of the study.

Exclusion Criteria:

• Pregnant women, women planning to become pregnant and breastfeeding women
• Subjects with a history of MS in first grade family members
• A history of or currently active clinically significant cardiac (including clinically significant ECG abnormalities in the opinion of the PI), pulmonary, gastrointestinal, hepatic, renal, pancreatic, or neurological disease
• ALT, AST and/or gamma-GT above 3 times the upper limit of normal
• Serum creatinine above 1.5 times the upper limit of normal
• Amylase above 1.5 times the upper limit of normal
• Hemoglobin < 7.0 mmol/L for females and < 8 mmol/L for males; leucocytes > 20*109/L or < 3.5*109/L; platelets < 125*109/L
• SBP > 160 mmHg and/or DBP > 100 mmHg
• Known or suspected hypersensitivity to any component of DC-TAB
• Known or suspected impairment of the immune system
• Acute respiratory or other active infections or illnesses
• Fever (oral temperature > 38.0 °C on day 1)
• Blood donation or significant blood loss within 90 days of first study medication dosing.
• Plasma donation within 7 days of first study medication dosing
• Recipients of blood or blood products in the last 6 months
• Participation in another clinical study within 90 days of the start of this trial or planning participation in another clinical trial during this study or in the 4 weeks after last visit
• Taking immunosuppressive agents, corticosteroids, anti-allergic, anti-coagulation or anti-platelet medication
• History of drug addiction (positive drug screen) or excessive use of alcohol (weekly intake more than 28 units of alcohol), or psychological or other emotional problems that are likely to invalidate informed consent, or limit the ability of the subject to comply with the protocol requirements
• Positive HIV1, or HIV2 serology
• Positive results from the hepatitis serology which indicates acute or chronic hepatitis B or hepatitis C
• Positive alcohol breath test
• Vaccination with any vaccine within 4 weeks prior to dosing of the study medication
• Any physical condition that would, in the opinion of the investigator, place the subject at an unacceptable health risk or risk of injury or render the subject unable to meet the requirements of the protocol
• History of serious adverse reactions or hypersensitivity to any medicinal product
• Smoking > 5 cigarettes/day or unable to refrain from smoking while confined to the CPU
• Use of prescription, over-the-counter (OTC), herbal supplements (excluding hormonal contraceptives, one-a-day vitamins, acetaminophen) within 14 days prior to the first dose of study drug).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: single dose 4 mg; a single intravenous injection of 4 mg DC-TAB	Biological: recombinant human alpha B-crystallin; intravenous injection; Other Names: HspB5; CRYAB; DC-TAB
Active Comparator: single dose 12.5 mg; a single intravenous injection of 12.5 mg DC-TAB	Biological: recombinant human alpha B-crystallin; intravenous injection; Other Names: HspB5; CRYAB; DC-TAB
Active Comparator: single dose 25 mg; a single intravenous injection of 25 mg DC-TAB	Biological: recombinant human alpha B-crystallin; intravenous injection; Other Names: HspB5; CRYAB; DC-TAB
Active Comparator: single dose 37.5 mg; a single intravenous injection of 4 mg DC-TAB	Biological: recombinant human alpha B-crystallin; intravenous injection; Other Names: HspB5; CRYAB; DC-TAB
Placebo Comparator: single dose placebo; a single intravenous injection of placebo	Other: placebo comparator; intravenous injection; Other Names: phosphate-buffered saline
Active Comparator: multiple dose 10 mg; three consecutive daily intravenous injections of 10 mg DC-TAB	Biological: recombinant human alpha B-crystallin; intravenous injection; Other Names: HspB5; CRYAB; DC-TAB
Active Comparator: multiple dose 25 mg; three consecutive daily intravenous injections of 25 mg DC-TAB	Biological: recombinant human alpha B-crystallin; intravenous injection; Other Names: HspB5; CRYAB; DC-TAB
Active Comparator: multiple dose 37.5 mg; three consecutive daily intravenous injections of 37.5 mg DC-TAB	Biological: recombinant human alpha B-crystallin; intravenous injection; Other Names: HspB5; CRYAB; DC-TAB
Placebo Comparator: multiple dose placebo; three consecutive daily intravenous injections of placebo	Other: placebo comparator; intravenous injection; Other Names: phosphate-buffered saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (adverse events)	Frequency of	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antigen-specific T-cell response	Strength of antigen-specific T-cell responses	28 days
Pharmacokinetics (serum levels of DC-TAB)	Serum levels of DC-TAB	24 h
Local tolerability (Injection site abnormalities)	Injection site abnormalities	28 days
Antibody responses	Serum levels of anti-DC-TAB antibodies	28 days

Collaborators and Investigators

• Sponsor: Delta Crystallon BV
• Investigators: Principal Investigator: Floris Höppener, PhD, MD, Syneos Health

Publications and helpful links

General Publications

• van Noort JM, Bsibsi M, Nacken PJ, Verbeek R, Venneker EH. Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial. PLoS One. 2015 Nov 23;10(11):e0143366. doi: 10.1371/journal.pone.0143366. eCollection 2015.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: May 1, 2015
• First Submitted That Met QC Criteria: May 12, 2015
• First Posted (Estimate): May 13, 2015

Study Record Updates

• Last Update Posted (Estimate): May 13, 2015
• Last Update Submitted That Met QC Criteria: May 12, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: alpha B-crystallin; immune tolerance
• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis
• Other Study ID Numbers: DC-001