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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Biological: recombinant human alpha B-crystallin
* Other: placebo comparator


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alpha B-crystallin, immune tolerance