Clinical Trials Register

Summary
EudraCT Number:	2010-018775-17
Sponsor's Protocol Code Number:	TRX4_DM_019_EU_10
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-10-21
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

Netherlands - Competent Authority

A.2

EudraCT number

2010-018775-17

A.3

Full title of the trial

DEFEND 2: Durable-Response Therapy Evaluation For
Early- or New-Onset Type 1 Diabetes

A.3.2

Name or abbreviated title of the trial where available

DEFEND-2

A.4.1

Sponsor's protocol code number

TRX4_DM_019_EU_10

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Tolerx, Inc.
B.1.3.4	Country	United States
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Otelixizumab
D.3.2	Product code	TRX4
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	881191-44-2
D.3.9.2	Current sponsor code	TRX4
D.3.9.3	Other descriptive name	Otelixizumab
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	0.2
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Monoclonal antibody

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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Type 1 Diabetes Mellitus

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10012608
E.1.2	Term	Diabetes mellitus insulin-dependent
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

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 is to demonstrate that subjects who receive an 8 day series of otelixizumab infusions have greater improvement than subjects who receive placebo in endogenous insulin secretion, as assessed by area under the concentration-time curve (AUC) for mixed meal-stimulated C peptide, at 12 months after study drug administration.

E.2.2

Secondary objectives of the trial

Secondary objectives are:
1. To assess exogenous insulin use for the otelixizumab and placebo groups and for selected subpopulations;
2. To assess glycemic control, as measured by HbA1c, subject-reported hypoglycemic events, and hypoglycemic and hyperglycemic excursions, for the otelixizumab and placebo groups and for selected subpopulations;
3. To assess the safety of an 8 day series of otelixizumab infusions, especially with regards to adverse events (AEs) and Epstein-Barr virus monitoring; and
4. To assess the pharmacodynamic (PD) effects of an 8 day series of otelixizumab infusions, especially with regards to absolute counts and percentages of lymphocyte subsets and CD3/T cell receptor (TCR) modulation.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. No condition that, in the investigator’s judgment, is likely to cause the subject to be unable to understand the information in the assent form or Informed Consent Document (ICD) or provide informed consent. Such conditions would include, but are not limited to, psychoses or mental retardation with an IQ below 65.
2. Informed Consent Document signed by the subject if the subject is legally an adult. If the subject is legally a minor, ICD signed by the subject’s parent, both parents, or guardian and assent form signed by the subject, in accordance with the regulatory and legal requirements of the participating country.
3. Male or female, aged 12 to 45 years, inclusive, at the time of anticipated first dose of study drug. In Denmark, subjects must be aged 18 to 45 years. Subjects aged 12 to 17 years must be Tanner Stage >= 2. All subjects must weigh at least 31 kg.
4. a. Diagnosis of diabetes mellitus according to ADA criteria (Appendix 1), with an interval of ≤ 90 days between the initial diagnosis and the first dose of study drug. Documentation of the diagnosis of DM, including the date of diagnosis, must be obtained from the diagnosing physician.
b. History and clinical course consistent with type 1a (autoimmune) DM.
5. Currently requires insulin for T1DM treatment, or has required insulin for DM at some time between the date of diagnosis and the first dose of study drug.
6. Willing to undergo intensive insulin therapy and to self-monitor blood glucose levels at least 4 times daily from Screening through Month 24 and 7 times daily before key visits.
7. Willing to record all insulin taken over 7 consecutive days during the 2 weeks before each key visit and to report this information using IVRS/IWRS. Also willing to record hypoglycemic events throughout the 2 years of the study.
8. Willing to remain at the study center on each day of dosing until all assessments are complete, or longer if deemed medically necessary by the investigator. Willing to remain at the study center to undergo the MMTT at intervals of 3-12 months.
9. Positive for one or more of the following autoantibodies typically associated with T1DM: antibody to glutamic acid decarboxylase (anti GAD); antibody to protein tyrosine phosphatase-like protein (anti IA 2); zinc transporter autoantibodies; insulin autoantibodies (IAA). A subject who is positive for IAA and negative for the other autoantibodies will not be eligible if the subject has used insulin for a total of 7 days or more.
10. Evidence of residual functioning β cells as measured by a stimulated C-peptide level over 0.20 nmol/L (0.6 μg/L) during an MMTT that was initiated when blood glucose level was > 70 mg/dL and ≤ 200 mg/dL
11. Maximum stimulated C-peptide level ≤ 3.50 nmol/L.
12. Body Mass Index (BMI) < 32.

E.4

Principal exclusion criteria

1. If of childbearing potential (defined as women who are premenopausal [have had at least 1 menstrual period during the past 1 year] and have not had a hysterectomy or tubal ligation) must use adequate contraception if sexually active.
2. Significant systemic infection during the 6 weeks before the first dose of study drug.
3. Current or prior malignancy, other than non-melanoma skin cancer (subject must have had fewer than 5 occurrences of non-melanoma skin cancer, and the last occurrence must not be within 3 months of study entry).
4. A positive intradermal skin test for tuberculosis using purified protein derivative (PPD).
5. Significant and/or active disease in any body system likely to increase the risk to the subject or interfere with the subject’s participation in or completion of the study.
6. Clinically significant abnormal laboratory values during the Screening period, other than those due to T1DM.
7. Positive results for Hepatitis B surface antigen and for antibodies to Hepatitis B core antigen, and Hepatitis C.
8. Positive results for antibodies to HIV I and II, and considered by the investigator to be at high risk for HIV infection.
9. EBV viral load of > 10,000 copies per 10.000.000 peripheral blood mononuclear cells (PBMCs) as determined by quantitative polymerase chain reaction (qPCR).
10. A positive result on the Rapid Plasma Reagin (RPR) test for syphilis.
11. Have used any investigational drug within the 3 months before the first dose of study drug, and planning to take any investigational drug for the planned duration of study participation (2 years after the last dose of study drug).
12. Have used any potent immunosuppressive agent (e.g., systemic high-dose corticosteroids on a chronic basis, methotrexate, cyclosporine, or anti-TNF agents) within the 30 days before the first dose of study drug, and expected to require such treatment within 3 months after the last dose of study drug. (Intranasal, inhaled, and topical corticosteroid medications are permitted if used at recommended dosages.)
13. Have received a vaccine within the 30 days before the first dose of study drug, and expected to require a vaccine during the dosing period or the 14 days after the last dose of study drug.
14. Have previously received otelixizumab or any other anti-CD3 monoclonal antibody, e.g., OKT3 (muromonab or Orthoclone®), ChAglyCD3, or hOKT3γ1 (teplizumab, also known as ala ala), and not willing to refrain from using any such antibody for the planned duration of study participation (2 years after the last dose of study drug).
15. Have previously received any anti-lymphocyte monoclonal antibody, such as anti-CD20, anti-thymocyte globulin (ATG), rituximab (Rituxan®), or alemtuzumab (Campath®), and planning to use any such antibody for the planned duration of study participation (2 years after the last dose of study drug).
16. Prior allergic reaction, including anaphylaxis, to any human, humanized, chimeric, or rodent antibody.
17. Condition or situation that, in the investigator’s judgment, is likely to cause the subject to be unable or unwilling to participate in study procedures or to complete all scheduled assessments.
18. No prior allergic reaction, including anaphylaxis, to any component of the study drug product, e.g., histidine, disodium edetate, or polysorbate 80.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is change from baseline in 2 hour mixed meal-stimulated C peptide AUC at Month 12.

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

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

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.8.3

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

100

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial has a data monitoring committee

Yes

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

Subjects will be followed for 24 months after receiving study drug.

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	Yes
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	Yes
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	25
F.4.2	For a multinational trial
F.4.2.1	In the EEA	158
F.4.2.2	In the whole clinical trial	363

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

2010-06-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-01-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-03-09

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