Trial Outcomes & Findings for A Safety and Tolerability Study of Otelixizumab in Thyroid Eye Disease (NCT NCT01114503)

Results Overview

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase \>=3 x upper limit of normal (ULN), and total bilirubin \>=2 x ULN or international normalized ratio \>1.5. The classification as potentially drug-related was done based on the investigator's judgment.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

2 participants

Primary outcome timeframe

Up to Month 24 (Long term follow-up)

Results posted on

2020-10-30

Participant Flow

The study was conducted at a single center in United Kingdom from 23 June 2010 to 29 August 2012.

A total of 2 participants were randomized in cohort A1 of the study. The study was early terminated due to the need of better understanding of an efficacious dose with otelixizumab from other clinical studies.

Participant milestones

Participant milestones
Measure	Otelixizumab Cohort A1 Eligible participants received a total intravenous (IV) dose of otelixizumab 3.1 milligram (mg) for 8 days. The planned dosing regimen was 0.1 mg on Day 1, 0.2 mg on Day 2, 0.3 mg on Day 3, 0.5 mg on Day 4 to Day 8. The study medication was administered each day for 2 hours (h). The rate of infusion was 0.05 milligram per hour (mg/h) on Day 1, 0.1 mg/h on Day 2, 0.15 mg/h on Day 3, 0.25 mg/h on Day 4 to Day 8. At the start of each cohort in Part A, 2 participants acted as sentinel participants and complete dosing (Days 1-8) before further participants were dosed with otelixizumab. The first sentinel participants completed all of their dosing days and there was a minimum of 24 h elapse before the second sentinel participant started the dosing regimen. Further participants commenced dosing with otelixizumab once 24 h elapsed from the second sentinel participant receiving the final dose of otelixizumab on Day 8. Subsequent participants were dosed concurrently.
Overall Study STARTED	2
Overall Study COMPLETED	2
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Safety and Tolerability Study of Otelixizumab in Thyroid Eye Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Otelixizumab Cohort A1 n=2 Participants Eligible participants received a IV dose of otelixizumab 3.1 mg for 8 days. The planned dosing regimen was 0.1 mg on Day 1, 0.2 mg on Day 2, 0.3 mg on Day 3, 0.5 mg on Day 4 to Day 8. The study medication was administered each day for 2 h. The rate of infusion was 0.05 mg/h on Day 1, 0.1 mg/h on Day 2, 0.15 mg/h on Day 3, 0.25 mg/h on Day 4 to Day 8. At the start of each cohort in Part A, 2 participants acted as sentinel participants and complete dosing (Days 1-8) before further participants were dosed with otelixizumab. The first sentinel participants completed all of their dosing days and there was a minimum of 24 h elapse before the second sentinel participant started the dosing regimen. Further participants commenced dosing with otelixizumab once 24 h elapsed from the second sentinel participant receiving the final dose of otelixizumab on Day 8. Subsequent participants were dosed concurrently.
Age, Continuous	53.5 Years n=93 Participants
Sex: Female, Male Female	1 Participants n=93 Participants
Sex: Female, Male Male	1 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants
Race (NIH/OMB) White	2 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants

PRIMARY outcome

Timeframe: Up to Month 24 (Long term follow-up)

Population: All Subjects Population included all participants who receive at least one dose of study medication.

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase \>=3 x upper limit of normal (ULN), and total bilirubin \>=2 x ULN or international normalized ratio \>1.5. The classification as potentially drug-related was done based on the investigator's judgment.

Outcome measures

Outcome measures
Measure	Otelixizumab Cohort A1 n=2 Participants Eligible participants received a IV dose of otelixizumab 3.1 mg for 8 days. The planned dosing regimen was 0.1 mg on Day 1, 0.2 mg on Day 2, 0.3 mg on Day 3, 0.5 mg on Day 4 to Day 8. The study medication was administered each day for 2 h. The rate of infusion was 0.05 mg/h on Day 1, 0.1 mg/h on Day 2, 0.15 mg/h on Day 3, 0.25 mg/h on Day 4 to Day 8. At the start of each cohort in Part A, 2 participants acted as sentinel participants and complete dosing (Days 1-8) before further participants were dosed with otelixizumab. The first sentinel participants completed all of their dosing days and there was a minimum of 24 h elapse before the second sentinel participant started the dosing regimen. Further participants commenced dosing with otelixizumab once 24 h elapsed from the second sentinel participant receiving the final dose of otelixizumab on Day 8. Subsequent participants were dosed concurrently.
Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event Any AE	2 Participants
Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event Any SAE	0 Participants
Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event Any drug-related (AE)	2 Participants

PRIMARY outcome

Timeframe: Up to Month 24 (Long term follow-up)

Population: All Subjects Population

The PCC range for clinical chemistry parameters included albumin, \<30 gram per liter (g/L); calcium, low- \< 2.0 millimole (mmol)/L: high-\>2.75 mmol/L; creatinine, high- \> 1.3x ULN mmol/L or \> 159 micromole (μmol)/L or \> 44 μmol/L change from Baseline; glucose, low- \< 3.0 mmol/L, high- \> 9.0 0 mmol/L; magnesium, low- \< 0.5 mmol/L, high- \> 1.23 mmol/L, phosphorus, low- \< 0.8 mmol/L, high- \> 1.6 mmol/L; potassium, Low- \< 3.0 mmol/L, high- \> 5.5 mmol/L; sodium, low- \< 130 mmol/L, high- \> 150 mmol/L; bicarbonate, low- \< 18 mmol/L, high- \> 32 mmol/L; alanine aminotransferase, high-\>= 2x ULN, where the normal range was (NR) 0 - 39 international units (IU)/L; aspartate aminotransferase, high- \>= 2x ULN, where NR was 0 - 39 IU/L; alkaline phosphatase, high- \>= 1.5x ULN, where NR was 35 - 120 IU/L; total bilirubin- \>= 1.5x ULN, where NR was 0 - 18 μmol/L.The assessments were done at Day 1 (pre dose), Day 8, Week 2-24 and Month 12 and 24.

Outcome measures

Outcome measures
Measure	Otelixizumab Cohort A1 n=2 Participants Eligible participants received a IV dose of otelixizumab 3.1 mg for 8 days. The planned dosing regimen was 0.1 mg on Day 1, 0.2 mg on Day 2, 0.3 mg on Day 3, 0.5 mg on Day 4 to Day 8. The study medication was administered each day for 2 h. The rate of infusion was 0.05 mg/h on Day 1, 0.1 mg/h on Day 2, 0.15 mg/h on Day 3, 0.25 mg/h on Day 4 to Day 8. At the start of each cohort in Part A, 2 participants acted as sentinel participants and complete dosing (Days 1-8) before further participants were dosed with otelixizumab. The first sentinel participants completed all of their dosing days and there was a minimum of 24 h elapse before the second sentinel participant started the dosing regimen. Further participants commenced dosing with otelixizumab once 24 h elapsed from the second sentinel participant receiving the final dose of otelixizumab on Day 8. Subsequent participants were dosed concurrently.
Number of Participants With Laboratory Clinical Chemistry Abnormalities Meeting the Criteria for Potential Clinical Concern (PCC)	0 Participants

PRIMARY outcome

Timeframe: Upto Month 24 (Long term follow-up)

Population: All Subjects Population

The PCC range for hematology parameters included white blood cell count, low- \< 3 giga cells (GI)/L, high- \> 20 GI/L; neutrophil count, low- \< 1.5 GI/L; hemoglobin, low- \> 25 g/L change from baseline, high- 180 g/L; hematocrit, low- \> 0.075 L change from baseline, high- 0.54 L; platelet count, low- \< 100 GI/L, high- \>550 GI/L and lymphocytes, low \< 0.8 GI/L. The assessments were done at Day 1 (pre dose), Day 8, Week 2-24, Month 12 and 24.

Outcome measures

Outcome measures
Measure	Otelixizumab Cohort A1 n=2 Participants Eligible participants received a IV dose of otelixizumab 3.1 mg for 8 days. The planned dosing regimen was 0.1 mg on Day 1, 0.2 mg on Day 2, 0.3 mg on Day 3, 0.5 mg on Day 4 to Day 8. The study medication was administered each day for 2 h. The rate of infusion was 0.05 mg/h on Day 1, 0.1 mg/h on Day 2, 0.15 mg/h on Day 3, 0.25 mg/h on Day 4 to Day 8. At the start of each cohort in Part A, 2 participants acted as sentinel participants and complete dosing (Days 1-8) before further participants were dosed with otelixizumab. The first sentinel participants completed all of their dosing days and there was a minimum of 24 h elapse before the second sentinel participant started the dosing regimen. Further participants commenced dosing with otelixizumab once 24 h elapsed from the second sentinel participant receiving the final dose of otelixizumab on Day 8. Subsequent participants were dosed concurrently.
Number of Participants With Laboratory Hematology Abnormalities Meeting the Criteria for PCC	0 Participants

PRIMARY outcome

Timeframe: Up to Month 24 (Long term follow-up)

Population: All Subjects Population

The urinalysis parameters included pH, glucose, protein, blood and ketones by dipstic and microscopy (if urine dipstick was positive for blood or protein). The assessments were done at Day 1 (pre dose), Day 8, Week 2-24, Month 12 and 24.

Outcome measures

Outcome measures
Measure	Otelixizumab Cohort A1 n=2 Participants Eligible participants received a IV dose of otelixizumab 3.1 mg for 8 days. The planned dosing regimen was 0.1 mg on Day 1, 0.2 mg on Day 2, 0.3 mg on Day 3, 0.5 mg on Day 4 to Day 8. The study medication was administered each day for 2 h. The rate of infusion was 0.05 mg/h on Day 1, 0.1 mg/h on Day 2, 0.15 mg/h on Day 3, 0.25 mg/h on Day 4 to Day 8. At the start of each cohort in Part A, 2 participants acted as sentinel participants and complete dosing (Days 1-8) before further participants were dosed with otelixizumab. The first sentinel participants completed all of their dosing days and there was a minimum of 24 h elapse before the second sentinel participant started the dosing regimen. Further participants commenced dosing with otelixizumab once 24 h elapsed from the second sentinel participant receiving the final dose of otelixizumab on Day 8. Subsequent participants were dosed concurrently.
Number of Participants With Laboratory Urinalysis Abnormalities Meeting the Criteria for PCC	0 Participants

PRIMARY outcome

Timeframe: Up to Week 24

Population: All Subjects Population

The following laboratory parameters were analyzed: thyroid function assessment (thyroid stimulating hormone \[TSH\], thyroid peroxidase antibody, thyrotropin receptor antibodies (TSH-R-Abs) or TSH-binding inhibiting immunoglobulin (TBII), free thyroxine \[fT4\], free triiodothyronine \[fT3\]; hormone and glucose assays (cortisol, adrenocorticotrophic hormone \[ACTH\], insulin-like growth factor \[IgF-1\] and plasma glucose. Thyroid function tests were done at Day 1 (pre-dose) and Week 4-24. Hormone and glucose assays were done at Day 1 (pre-dose) and Week 2-24.

Outcome measures

Outcome measures
Measure	Otelixizumab Cohort A1 n=2 Participants Eligible participants received a IV dose of otelixizumab 3.1 mg for 8 days. The planned dosing regimen was 0.1 mg on Day 1, 0.2 mg on Day 2, 0.3 mg on Day 3, 0.5 mg on Day 4 to Day 8. The study medication was administered each day for 2 h. The rate of infusion was 0.05 mg/h on Day 1, 0.1 mg/h on Day 2, 0.15 mg/h on Day 3, 0.25 mg/h on Day 4 to Day 8. At the start of each cohort in Part A, 2 participants acted as sentinel participants and complete dosing (Days 1-8) before further participants were dosed with otelixizumab. The first sentinel participants completed all of their dosing days and there was a minimum of 24 h elapse before the second sentinel participant started the dosing regimen. Further participants commenced dosing with otelixizumab once 24 h elapsed from the second sentinel participant receiving the final dose of otelixizumab on Day 8. Subsequent participants were dosed concurrently.
Number of Participants With Thyroid Function Assessment, Hormone and Glucose Assay Abnormalities Meeting the Criteria for PCC	0 Participants

PRIMARY outcome

Timeframe: Up to Month 24 (Long term follow-up)

Population: All Subjects Population

Vital signs assessment included pulse rate, blood pressure, temperature and respiratory rate. Criteria for vital sign values meeting potential clinical concern included: supine pulse rate \<40 or \>110 beats per minute (bpm), \>= 15 increase from baseline and \>= 30 decrease from baseline; systolic blood pressure (SBP) \< 85 and \> 160 millimeters of mercury (mm Hg), \>= 20 mmHg increase from baseline and \>= 40 mmHg decrease from baseline; diastolic blood pressure (DBP) \< 45 and \> 100 mm Hg, \>= 10 mmHg increase from baseline and \>= 20 mmHg decrease from baseline.

Outcome measures

Outcome measures
Measure	Otelixizumab Cohort A1 n=2 Participants Eligible participants received a IV dose of otelixizumab 3.1 mg for 8 days. The planned dosing regimen was 0.1 mg on Day 1, 0.2 mg on Day 2, 0.3 mg on Day 3, 0.5 mg on Day 4 to Day 8. The study medication was administered each day for 2 h. The rate of infusion was 0.05 mg/h on Day 1, 0.1 mg/h on Day 2, 0.15 mg/h on Day 3, 0.25 mg/h on Day 4 to Day 8. At the start of each cohort in Part A, 2 participants acted as sentinel participants and complete dosing (Days 1-8) before further participants were dosed with otelixizumab. The first sentinel participants completed all of their dosing days and there was a minimum of 24 h elapse before the second sentinel participant started the dosing regimen. Further participants commenced dosing with otelixizumab once 24 h elapsed from the second sentinel participant receiving the final dose of otelixizumab on Day 8. Subsequent participants were dosed concurrently.
Number of Participants With Vital Signs Abnormalities Meeting the Criteria for PCC	0 Participants

PRIMARY outcome

Timeframe: Screening (Day -35 to Day -1)

Population: All Subjects Population

ECG parameters included pulse rate (PR) interval, QRS interval, QT interval, corrected QT interval using Bazett's formula (QTcB) and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval \<110 and \>220 milliseconds (msec); QRS interval \<75 and \>110 msec; QTc interval \>480 to \<= 500 msec, increase from baseline QTc \>30 to \<= 60 msec.

Outcome measures

Outcome measures
Measure	Otelixizumab Cohort A1 n=2 Participants Eligible participants received a IV dose of otelixizumab 3.1 mg for 8 days. The planned dosing regimen was 0.1 mg on Day 1, 0.2 mg on Day 2, 0.3 mg on Day 3, 0.5 mg on Day 4 to Day 8. The study medication was administered each day for 2 h. The rate of infusion was 0.05 mg/h on Day 1, 0.1 mg/h on Day 2, 0.15 mg/h on Day 3, 0.25 mg/h on Day 4 to Day 8. At the start of each cohort in Part A, 2 participants acted as sentinel participants and complete dosing (Days 1-8) before further participants were dosed with otelixizumab. The first sentinel participants completed all of their dosing days and there was a minimum of 24 h elapse before the second sentinel participant started the dosing regimen. Further participants commenced dosing with otelixizumab once 24 h elapsed from the second sentinel participant receiving the final dose of otelixizumab on Day 8. Subsequent participants were dosed concurrently.
Number of Participants With Electrocardiogram (ECG) Abnormalities Meeting the Criteria for PCC	0 Participants

PRIMARY outcome

Timeframe: Week 2 to Week 12

Population: All Subjects Population

The PCC range for EBV viral load was \> 10,000 copies of deoxyribonucleic acid (DNA) per million lymphocytes. The assessments were done at Week 2, Week 4, Week 8 and Week 12.