Clinical Trials Register

Summary
EudraCT Number:	2008-002205-40
Sponsor's Protocol Code Number:	OTX115495 (DEFEND-1 EU)
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-07-07
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2008-002205-40

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Durable response therapy evaluation for early or new onset type 1 diabetes mellitus

A.3.2

Name or abbreviated title of the trial where available

DEFEND-1

A.4.1

Sponsor's protocol code number

OTX115495 (DEFEND-1 EU)

A.5.4

Other Identifiers

Name:

DEFEND-1

Number:

OTX115495 (DEFEND-1 EU)

A.7

Trial is part of a Paediatric Investigation Plan

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	GlaxoSmithKline
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline
B.5.2	Functional name of contact point	EU GSK Clinical Trials Call Centre
B.5.3	Address:
B.5.3.1	Street Address	1-3 Ironbridge Road
B.5.3.2	Town/ city	Uxbridge
B.5.3.3	Post code	UB11 1BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0044 208990 4466
B.5.5	Fax number	0044208966 5970
B.5.6	E-mail	GSKClinicalSupportHD@gsk.com
B.Sponsor: 2
B.1.1	Name of Sponsor	GlaxoSmithKline
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor
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	GSK2136525
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
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	GSK 2136525
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	5
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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.8.3	Pharmaceutical form of the placebo	Solution for infusion
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

Otelixizumab is being developed for the treatment of patients with autoimmune T1DM with residual beta cell function (RBCF), with the goal of preserving RBCF in this patient population. There are currently no approved treatments for this indication.
Approved treatments for T1DM in the EU are insulins or insulin analogues.

E.1.1.1

Medical condition in easily understood language

Type 1 Diabetes

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
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

Yes

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, 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), hypoglycemic and hyperglycemic excursions, and Epstein-Barr virus monitoring; and
4. To assess the pharmacodynamic effects of an 8-day series of otelixizumab infusions, especially with regards to absolute counts and percentages of lymphocyte subsets, CD3/T cell receptor (TCR) saturation and modulation, and serum levels of cytokines and cellular mediators.

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 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. 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 and WHO 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.
4.b*. History and clinical course consistent with type 1a (autoimmune) DM.
5.Currently requires insulin treatment for T1DM, or has required insulin for DM treatment 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 over 7 consecutive days during the 2 weeks before the visits at Baseline, Week 12, and Months 6, 12, 18, and 24.
7.Willing to record home insulin use, blood glucose levels, and signs and symptoms of hypoglycemic excursions using an electronic personal device assistant, complying with all data transmission requirements, for the planned duration of study participation (2 years after the last dose of study drug).
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 mixed meal tolerance test (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 insulin autoantibodies (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 > 0.20 nmol/L during the Screening or Predose MMTT when blood glucose level is > 70 mg/dL and ≤ 200 mg/dL.
11.Maximum stimulated C-peptide level ≤ 3.50 nmol/L.
12.For subjects aged 18 years or older at Screening, Body Mass Index (BMI) < 32. For subjects under 18 at Screening, BMI < 95th percentile for age and sex according to United States Center for Disease Control and Prevention.
If a potential subject is identified who is in generally good health other than T1DM, and for whom non contraindicating medical issues exist, yet who does not strictly meet all eligibility criteria, the Sponsor reserves the right to allow participation in the study after review and discussion of the patient's medical status with the Investigator and the Medical Monitor and if they are in agreement with this decision.

E.4

Principal exclusion criteria

1. Pregnant, breastfeeding, or planning to become pregnant during the 60 days after the last dose of study drug.
2. 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), not using adequate contraception if sexually active.
3. Significant systemic infection during the 6 weeks before the first dose of study drug.
4. 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 history of current within 3 months of study entry).
5. History of current or past active tuberculosis infection or latent tuberculosis infection. This can be met with a positive purified protein derivative (PPD) test result during Screening or a documented positive result within 6 months prior to dosing.
6. 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.
7. Clinically significant abnormal laboratory values during the Screening period, other
than those due to T1DM.
8. Positive results for Hepatitis B surface antigen and for antibodies to Hepatitis B core antigen, and Hepatitis C.
9. Positive results for antibodies to HIV I and II, and considered by the investigator to be at high risk for HIV infection.
10. EBV viral load of > 10,000 copies per 10ex6 peripheral blood mononuclear cells (PBMCs) as determined by quantitative polymerase chain reaction (qPCR). If there is any clinical suspicion that a subject who is EBV seronegative and with EBV PCR < 10,000 copies per 10ex6 PBMCs has symptoms consistent with infectious mononucleosis prior to administration of study drug, then a monospot test result must be positive.
11. A positive result on the Rapid Plasma Reagin (RPR) test for syphilis; or, if result of RPR test is positive, a negative confirmatory test (for example, fluorescent treponemal antibody absorbed [FTA-ABS] test).
12. 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).
13. 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.)
14. 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 the study drug.
15. Have previously received otelixizumab or any other anti-CD3 monoclonal antibody, e.g., OKT3 (muromonab or Orthoclone®), ChAglyCD3, or hOKT3γ1 (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).
16. Have previously received any anti-lymphocyte monoclonal antibody, such as anti-
CD20, anti-thymocyte globulin (ATG), rituximab (Rituxan®), or alemtuzumab
(Campath®), and not planning to use any such antibody for the planned duration of study participation (2 years after the last dose of study drug).
17. Prior allergic reaction, including anaphylaxis, to any human, humanized, chimeric, or rodent antibody.
18. 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.

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. Mixed meal-stimulated C-peptide AUC at Week 12 and Months 6, 18 and 24 will be analyzed using the same approach. C-peptide AUC change status (decreased, unchanged, or increased from baseline) will also be assessed at Week 12 and months 6, 12, 18 and 24.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 Months

E.5.2

Secondary end point(s)

Responder status (HbA1c <6.5%, insulin use ,0.5IU/kg/Day), mean daily insulin use, HbA1c, incidence of hypoglycaemic events, number and magnitude of hypoglycaemic excursions

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 12, Month 6, 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.8.2.4

Number of treatment arms in the trial

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

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

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

Canada

Denmark

Finland

Germany

Italy

Spain

Sweden

United Kingdom

United States

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. When data are available from all subjects through Month 18, a report will be issued to summarize the results trhough Month 18. Follow-up data thorugh Month 24 will be summarized in a supplemental report.

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

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

243

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

240

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

No further treatment with study agent planned. There will be a request for all subjects to sign a new ICF to allow follow-up to 48 months post dosing. See separate statement please.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2008-08-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-07-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-01-31

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials