| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| NOT1DM is an autoimmune disease. This means that the immune system, the part of the body which usually helps to fight infections, mistakenly attacks cells that produce insulin in the body. Insulin is necessary for the uptake of sugar from the blood |
|
| E.1.1.1 | Medical condition in easily understood language |
| NOT1DM is an autoimmune disease. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003814 |
| E.1.2 | Term | Autoimmune disease, not elsewhere classified |
| E.1.2 | System Organ Class | 100000004870 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the effect of a single course of otelixizumab treatment on the acute and long term safety and tolerability of otelixizumab in NOT1DM patients. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives (Pharmacokinetic)
-To assess the pharmacokinetics of repeat dose administration of otelixizumab over 14 days in NOT1DM patients.
Secondary Objectives (Efficacy)
-To assess the effect of a single course of otelixizumab treatment on the rate of decline of pancreatic Beta-cell function over 24 months in NOT1DM patients.
-To assess the effect of a single course of otelixizumab treatment on the rate of decline of C-peptide response and insulin
sensitivity of Beta-cell function determined after a hyperglycemic clamp over 24 months in NOT1DM patients.
-To assess the effect of a single course of otelixizumab treatment on exogenous insulin use for otelixizumab over 24 months in NOT1DM patients.
-To assess the effect of a single course of otelixizumab treatment on glycaemic control over 24 months in NOT1DM patients.
Secondary Objectives (Pharmacodynamic)-Please refer to protocol P 21-22 for further information.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Male or female aged between 16 and 27 years of age inclusive, at the time of signing the informed consent.
NOTE: Subjects aged 16 to 17 years must be Tanner Stage ≥ 2 (see SPM). All subjects must weigh at least 31 kg.
2. Diagnosis of diabetes mellitus according to ADA and WHO criteria and consistent with Type 1a (autoimmune) DM, with an interval of approximately 28 days (not more than 32 days) between the initial diagnosis and the first dose of study drug).
Written documentation of the diagnosis of DM, including the date of diagnosis, must be obtained from the diagnosing physician.
3. Currently requires insulin treatment for T1DM and has received insulin therapy for at least 7 days prior to screening.
4. Positive for at least one autoantibody associated with T1DM:
antibody to glutamic acid decarboxylase (anti GAD), antibody to protein tyrosine phosphatase-like protein (anti IA 2), antibody to islet-cell antigen (ICA) or ZnT8 Autoantibody.
5. Evidence of residual functioning β cells as measured by mixed meal stimulated C peptide peak level ≥ 0.2 nmol/L.
6. A female subject is eligible to participate if she has a negative pregnancy test as determined by a urine hCG test at screening or prior to dosing AND
- Agrees to use one of the contraception methods listed in Section 4.3.1. Female subjects must agree to use contraception for 2 weeks prior to dosing and for 60 days after the last dose of study drug.
- OR has only same-sex partners (refrains from heterosexual intercourse), when this is her preferred and usual lifestyle.
7. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in Section 4.3.1. This criterion must be followed from 2 weeks prior to dosing and for 60 days after the last dose of study drug.
8. Willing to follow the procedures outlined in the protocol.
9. AST and ALT < 2xULN; alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
10. Subjects eligible for enrolment in the study must meet all of the following criteria:
- QTc <450msec or
- QTc <480msec for patients with bundle branch block
The QTc is the QT interval corrected for heart rate according to either Bazett’s formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.
- For subject eligibility and withdrawal, QTcF will be used.
- For purposes of data analysis, QTcF will be used as primary.
The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period.
11. Screening total lymphocyte counts within the normal range in two separate samples taken at least three days apart (eg screening and Day -1).
12. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. In the case of minors (under 18 years) written informed consent must also be obtained from a parent or Legally Acceptable Representative (LAR). |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. A positive pre-study Hepatitis B surface antigen or core antibody or positive
Hepatitis C antibody result within 3 months of screening.
2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
3. A positive test for HIV 1 and/or 2 antibody.
4. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
5. Exposure to more than four new investigational drugs within 12 months prior to the first dosing day.
6. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or CRO/GSK Medical Monitor, contraindicates their participation.
7. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 3 month period.
8. Lactating females.
9. Subject is mentally or legally incapacitated.
10. History of thrombocytopenia.
11. The subject has received immunization with a vaccine within 4 weeks before the first dose of study drug or requires a vaccine within 30 days after the last dose of study drug
12. The subject has had significant systemic infection during the 6 weeks before the first dose of study drug (e.g., infection requiring hospitalisation, major surgery, or i.v. antibiotics to resolve; other infections, e.g., bronchitis, sinusitis, localised cellulitis, candidiasis, or urinary tract infections, must be assessed on a case-by-case basis by the investigator regarding whether they are serious enough to warrant exclusion).
13. Current or prior malignancy, other than non-melanoma skin cancer.
14. Patient has undergone a splenectomy
15. Radiological evidence of active tuberculosis (TB).
16. 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. Examples of significant diseases include, but are not limited to, coronary artery disease, congestive heart failure, uncontrolled hypertension, renal failure, emphysema, history of bleeding peptic ulcers, history of seizure(s), addiction to illicit drugs, and alcohol abuse.
17. Clinically significant (based on Investigator’s discretion in consultation with the Medical Monitor if second opinion required) abnormal laboratory values during the screening period, other than those due to T1DM. A clinically significant abnormal value will not result in exclusion if, upon retest, the abnormality is resolved or becomes clinically insignificant.
18. Positive EBV capsid Ab IgM in absence of a positive EBV EBNA Ab IgG
19. EBV viral load of> 10,000 copies per 106 peripheral blood mononuclear cells
(PBMCs) as determined by quantitative polymerase chain reaction (qPCR)..
20. IgG negative for EBV.
21. A positive result on a test for syphilis; and if result of the first test is positive, then a confirmatory test using another method will be performed.
22. Have used any atypical antipsychotic drug (e.g., risperidone [Risperdal], quetiapine [Seroquel], or clozapine [Clozaril]) within the 30 days before signing the ICF.
23. Have previously received otelixizumab or any other anti CD3 monoclonal antibody,
e.g., OKT3 (muromonab or Orthoclone), ChAglyCD3, or hOKT3γ1 (ala ala), and are 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).
24. Previous or current exposure to biologic cell-depleting therapies (e.g. anti-CD11a, anti-CD22, anti-CD20, anti-BLyS/BAFF, anti-CD3, anti-CD5, anti-CD52) including investigational agents, and planning to use any such antibody for the planned duration of study participation (2 years after the last dose of study drug).
25. Predisposition to thromboembolic disease, or thromboembolic event (excluding superficial) in the past 12 months.
26. Is currently receiving corticoid treatment or has received systemic corticoid
treatment within a month of screening.
27. History of Graves disease
28. Prior allergic reaction, including anaphylaxis, to any human, humanised, chimeric, or rodent antibody.
29. Have undergone any major surgical procedure within 30 days before the first dose of study drug, and/or planning to undergo any such surgery within 3 months after the last dose of study drug.
30. Any 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) |
• Incidence of adverse events (AEs) particularly those related to Cytokine release syndrome (CRS)
• Epstein-Barr virus (EBV) reactivation
• Changes in laboratory values, electrocardiograms (ECGs) and vital signs
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetic:
-Free serum otelixizumab concentrations
over Days 1-14 and summary PK
parameters.
Efficacy:
- Change from baseline in C-peptide and glucose AUC (0-120) after a Mixed Meal Tolerance Test at Month 3, 6, 12, 18 and 24.
- Change from baseline in C-Peptide AUC and glucose hyperglycemic phase [H60 to H140 minutes] and insulin sensitivity (IS) index after a hyperglycemic clamp at Months 6 and 24.
- Change from baseline in mean daily insulin use over 7 consecutive days during the week preceding all visits or phone calls.
- Change from baseline in HbA1c level
- Body weight Day -1, Months 12-24,
-Hypoglycemic and hyperglycemic events over Months 1-24.
Pharmacodynamic:
- Relative change from baseline (%) in CD4+ and CD8+ cells, free CD3 and
bound otelixizumab on CD4+ and CD8+ cells on Days 1 through 14.
- Change from baseline in anti-drug antibody levels at Months 3 and 6.
Exploratory Endpoints
- Change from baseline in absolute
lymphocyte counts and subsets (CD3+
CD4+, CD3+ CD8+, and CD19+ cells) and
phenotype (eg effector, memory, regulatory
T cells, eg CD45RA, CCR7+) over week 6 to Month 24.
- Change from baseline in demethylated
FoxP3 expression in whole blood over week 6 to Month 24.
- Change from baseline in absolute numbers
of HLA-A2-restricted CD8 T lymphocytes
reactive to specific auto-antigens (by
multimer) over week 6 to Month 24.
- Change from baseline in frequency of
cytokine producing cells following in vitro
stimulation with auto-antigens (by
ELISPOT) over week 6 to Month 24.
- Change from baseline in auto-antibody
titres (using a panel of common autoantibodies
associated with T1DM antigens
and possibly other auto-antigens) and
serum analytes (such as cytokines/
chemokines) over week 6 to Month 24.
- Change from baseline in T cell clonal
repertoire by TCR deep sequencing over week 6 to Month 24.
- Change from baseline in serum by
measuring relative levels of unmethylated
INS DNA and/or other biomarkers for -
cell death in serum over week 6 to Month 24.
- Change from baseline in relative levels of
T lymphocyte suppression using micro
suppression assay over week 6 to Month 24.
Follow up Endpoints (Data Collected at
Month 36, 48 & 60 if Available)
- Significant adverse events.
- Severe (as per ADA classification,
Appendix 7) hypoglycemic events which
occurred between Months 24 up to 60.
- Severe hyperglycemic events which occurred between Months 24 up to 60.
- Mean daily insulin use over 7 consecutive
days preceding the call.
- HbA1C results around time of the phone
call. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Over Months 1-24 unless otherwise specified
Follow up Endpoints (Data Collected at
Month 36, 48 & 60 if Available) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Is a dose escalating study - dose groups will be sequentially run |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| 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 | |
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