TRX4 Monoclonal Antibody in Type 1 Diabetes (T1 DM)

Levels of cytokines: interferon (IFN)-gamma, interleukin (IL)-10, IL-6 and tumor necrosis factor (TNF)-alpha were assessed. One sample was collected at Baseline, on dose Day 1 at 1, 2, 3, and 8 hours post-end of infusion (EOI) and on all other dosing days at pre-dose, and 1, 2, 3, and 8 hour post-EOI. After the completion of dosing, on Day 21 and Week 8, only the IL-10 level was assessed in the cytokine blood sample.

Time frame: Up to Week 8

Population: All subjects Population. Only those participants available for analysis for the particular parameter are presented. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group.

Clinical chemistry parameters: alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, gamma-glutamyl transferase, lactate dehydrogenase, lipids, blood urea nitrogen, creatinine, uric acid, sodium, potassium, chloride, carbon dioxide, creatinine phosphokinase, albumin, calcium, magnesium, glucose, phosphate, bicarbonate and total protein were assessed for abnormal PCC values. Data for abnormal parameters (high and low) is presented. Only those parameters for which at least one value of PCC was reported are summarized.

Time frame: Up to Month 48

Population: All subjects Population. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group.

Hematology parameters: hemoglobin, white blood cell (WBC) count, basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelet count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were assessed for abnormal PCC values. Data for abnormal parameters (high and low) is presented. Only those parameters for which at least one value of PCC was reported are summarized.

Time frame: Up to Month 48

Population: All subjects Population. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group.

Urinalysis parameters: Occult blood, Glucose urine, Ketones, Leukocyte esterase, Nitrite, pH, Protein urine were assessed. Abnormal values for occult blood and ketones were presented as 1+, 2+ and 3+ (the plus sign increases with a higher level of parameters: 1+=slightly positive, 2+=positive, 3+=high positive). Abnormal glucose urine values were presented as 50, 100, 250 and 1000 mg/dL. Abnormal nitrite values were presented as 'positive', and abnormal urine protein values were presented as 30 and 100 mg/dL.

Time frame: Up to Month 48

Population: All subjects Population. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group.

AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include adverse events that result in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Time frame: Up to Month 24

Population: The 'All Subjects population' was defined as all participants who received at least one dose of study medication and was used in all study population and safety analyses. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group.

AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Cytokine release AEs were defined as occurring during dosing or within a limited time window after the last dose.

Time frame: Up to Month 24

Population: All subjects Population. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group.

EBV load was measured using quantitative polymerase chain reaction (PCR) method. If a participant had an EBV viral load of \>100,000 copies/10\^6 peripheral blood mononuclear cells (c/10\^6 PBMC) lymphocytes at any time post-dose, the test was repeated immediately. Data for participants with abnormal viral load is presented.

Time frame: Up to Month 18

Population: All subjects Population. Only those participants available at the specified time points were analyzed. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group.

Samples were planned to analyze at the screening visit and at Baseline. Further on dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months.

Time frame: At the screening visit and at Baseline. On dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months.

Population: PD summary Population. Data was not collected for this endpoint.

Pharmacokinetic (PK) samples were obtained at Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-SOI. On Dose Day 5, samples were collected at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI. The lower limit of quantification was 0.019 micrograms per milliliter (µg/mL). The 'PK summary Population' was defined as participants in the 'All Subjects' Population for whom a pharmacokinetic sample was obtained and analyzed, and who received the full scheduled dose, as specified in the protocol. Only those participants available at the specified time points were analyzed.

Time frame: At Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-start of infusion (SOI). On Dose Day 5, at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI.

Population: PK summary Population. A limited comparison of the PK of free serum otelixizumab in adolescents and adults was attempted using the cumulative 3.1 mg dose regimen. However, there were insufficient quantifiable concentrations obtained in either group to allow meaningful conclusions to be drawn. Data for only quantifiable concentration is presented.

Samples were planned to analyze at the Screen visit and at Baseline. Further on dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months.

Time frame: At the Screen visit and at Baseline. On dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months.

Population: PD summary Population. Data was not collected for this endpoint.

Participants were seen weekly during the first 4 weeks post-dose and then every other week through Week 12. After Week 12, visits occurred every 1 to 3 months through Month 18, which completes the Core Study up to Month 48 (follow up). Day 1 pre-dose value was considered as Baseline value. Change from Baseline was post-Baseline value minus Baseline value.

Time frame: Baseline and up to Month 48

Population: PD summary Population. Only those participants available at the specified time points were analyzed. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group. Data for only quantifiable concentration is presented.

PK samples were obtained at Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-SOI. On Dose Day 5, samples were collected at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI. The lower limit of quantification was 0.019 µg/mL. Only those participants available at the specified time points were analyzed.

Time frame: At Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-SOI. On Dose Day 5, at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI.

Population: PK summary Population. A limited comparison of the PK of free serum otelixizumab in adolescents and adults was attempted using the cumulative 3.1 mg dose regimen. However, there were insufficient quantifiable concentrations obtained in either group to allow meaningful conclusions to be drawn. Data for only quantifiable concentration is presented.

One sample was collected at the screening visit and at Baseline. On dose Day 1, samples were collected at EOI and 4 hour post-SOI. On all other dosing days, samples were collected at pre-dose, EOI and 4 hour post-SOI. CD4+/CD8+ ratio was determined by dividing the absolute count of CD4+ T cells by the absolute count of CD8+ T cells for the same participant at the same time point. The data was collected on Baseline, Days 1 to 8, Days 14, 21, 28, Weeks 6, 8, 10, 12, Months 4, 5, 6, 12, 24, 36 and 48. However data for Days 8 and 28 is presented.

Time frame: Day 8 and 28

Population: PD summary Population. Only those participants available at the specified time points were analyzed. Data for only quantifiable concentration is presented.

One sample was collected at the screening visit and at Baseline. On dose Day 1, samples were collected at EOI and 4 hour post-SOI. On all other dosing days, samples were collected at pre-dose, EOI and 4 hour post-SOI. To obtain absolute counts for each lymphocyte subset (CD19+ B cells, CD4+CD25hiFoxP3+ T cells, CD8+CD25+FoxP3+ T cells) the proportion of total lymphocytes constituting that subset was multiplied by the total count for the same participant at the same time point. The data was collected on Baseline, Days 1 to 8, Days 14, 21, 28, Weeks 6, 8, 10, 12, Months 4, 5, 6, 12, 24, 36 and 48. However data for Days 8 and 28 is presented. The 'Pharmacodynamic (PD) summary population' was defined as participants in the 'All Subjects' Population for whom a PD sample was obtained and analyzed and who received the full scheduled dose, as specified in the protocol.

Time frame: Day 8 and 28

Population: Only those participants available at the specified time points were analyzed. Data for only quantifiable concentration is presented.

One sample was collected at the screening visit and at Baseline. On dose Day 1, samples were collected at EOI and 4 hour post-SOI. On all other dosing days, samples were collected at pre-dose, EOI and 4 hour post-SOI. To obtain absolute counts for each lymphocyte subset (CD4+ T cells, CD8+ T cells) the proportion of total lymphocytes constituting that subset was multiplied by the total count for the same participant at the same time point. The data was collected on Baseline, Days 1 to 8, Days 14, 21, 28, Weeks 6, 8, 10, 12, Months 4, 5, 6, 12, 24, 36 and 48. However data for Days 8 and 28 is presented.

Time frame: Day 8 and 28

Population: PD summary Population. Only those participants available at the specified time points were analyzed. Data for only quantifiable concentration is presented.

Anti-otelixizumab antibody levels were determined by ELISA. Immunogenicity data was not collected for Cohort 5 (5 day dosing) participants.

Time frame: Up to Month 48

Population: All subjects Population. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group. Immunogenicity data was not collected for Cohort 5 (5 day dosing) participants.

Ibuprofen (analgesic) was given orally as follows: 400-800 mg 2 hour before SOI, 400-800 mg 2 hour after SOI, 400-800 mg 6 hour after SOI, and 400-800 mg at bedtime. If ibuprofen was contraindicated, acetaminophen was used in place of ibuprofen. Acetaminophen doses were adjusted so as it did not exceed 1000 mg per 6 hour or 4000 mg per day. A non-sedating antihistamine (cetirizine) was administered approximately 1 hour prior to each infusion of study drug. The recommended initial dose of cetirizine was 5 mg or 10 mg per day in adults and children aged 12 years and older. Normal saline solution was administered IV as needed to maintain hydration.

Time frame: Up to Day 8

Population: All subjects Population. Only those participants available at the specified time points were analyzed. Participants from all 7 cohorts who had received a total dose \<3.0 mg were analyzed as a separate treatment group.

One sample was collected at the screening visit and at Baseline. On dose Day 1, samples were collected at EOI and 4 hour post-SOI. On all other dosing days, samples were collected at pre-dose, EOI and 4 hour post-SOI. The data was collected on Baseline, Days 1 to 8, Days 14, 21, 28, Weeks 6, 8, 10, 12, Months 4, 5, 6, 12, 24, 36 and 48. However data for Days 8 and 28 is presented.

Time frame: Day 8 and 28

Population: PD summary Population. Only those participants available at the specified time points were analyzed. Data for only quantifiable concentration is presented.

Samples were planned to analyze at the screening visit and at Baseline. Further on dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months.

Time frame: At the screening visit and at Baseline. On dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months.

Population: PD summary Population. Data was not collected for this endpoint.

PK samples were obtained at Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour SOI. On Dose Day 5, samples were collected at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI. The lower limit of quantification was 0.019 µg/mL. Only those participants available at the specified time points were analyzed.

Time frame: At Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-SOI. On Dose Day 5, at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI.

Population: PK summary Population. A limited comparison of the PK of free serum otelixizumab in adolescents and adults was attempted using the cumulative 3.1 mg dose regimen. However, there were insufficient quantifiable concentrations obtained in either group to allow meaningful conclusions to be drawn. Data for only quantifiable concentration is presented.