Graves OphthalmopathyPhase 2NCT01114503
A Safety and Tolerability Study of Otelixizumab in Thyroid Eye Disease
A Phase 2 study testing Otelixizumab - low dose, Otelixizumab - medium low dose and Otelixizumab - medium high dose in people with Graves Ophthalmopathy, run by GlaxoSmithKline at 1 site in United Kingdom.
Trial summary
The purpose of this study is to investigate the safety and tolerability of otelixizumab in patients with Graves' ophthalmopathy (thyroid eye disease). There is currently no alternative therapy available for this condition other than treatment with steroids, or radiotherapy and surgery. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Graves Ophthalmopathy
- What is being tested?
- Otelixizumab - low dose, Otelixizumab - medium low dose and Otelixizumab - medium high dose
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 7 Jul 2010to 29 Aug 2012
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female between 18 and 75 years of age inclusive
- A female subject is eligible to participate if she is of:
- Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 mIU/ml and estradiol <40 pg/ml (<140 pmol/L) is confirmatory].
- Child-bearing potential and agrees to use one of the agreed contraception methods listed in the protocol for an appropriate period of time to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception for at least 2 weeks prior to dosing and for at least 6 months after the last dose.
- Male subjects must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until at least 60 days after the last dose.
- Blood test of liver function within normal range
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- Body mass index within 18.5 - 35 kg/m2 inclusive
- Capable of giving informed consent and agreement to comply with the study restrictions
- 12-lead ECG within normal limits
- fT4 blood levels within reference range for at least 2 months
- Active Graves' Ophthalmopathy (GO) with a Clinical Activity Score (CAS) of >/= 3 out of 7
- Moderately severe GO (as defined by EUGOGO guidelines)
- No previous immunosuppressive treatment for GO
- Subject is seropositive for EBV with <10,000 copies of EBV DNA per 10^6 lymphocytes (qPCR) or seronegative with no evidence of acute EBV infection (asymptomatic, negative EBV IgM and EBV viral load of <10,000 per 10^6 lymphocytes)
- The subject has no 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)
Who cannot join
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
- Positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines
- Positive test for HIV antibody
- Positive test for syphilis
- History of regular alcohol consumption within 6 months of the study defined as:
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- an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or
- an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females)
- Participation 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) or planning to take any investigational drug for the planned duration of study participation (6 months after the last dose of study drug)
- Exposure to more than four new chemical entities within 12 months prior to the first dosing day
- 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 GSK Medical Monitor, contraindicates their participation
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
- Pregnant females as determined by positive (serum or urine) hCG test at screening or prior to dosing, or lactating females
- Currently receiving or has received corticosteroids or other immunosuppressive agents within the last 3 months
- Evidence of optic neuropathy and/or corneal breakdown
- Immunization with a vaccine within 30 days before the first dose of study drug or requires a vaccine within 30 days after the last dose of study drug
- A CD4+ lymphocyte count outside the range of 0.53 - 1.76 × 109/L during screening
- Significant systemic infection during the 6 weeks before the first dose of study drug
- Received a course of oral antibiotics within 2 weeks of dosing day one
- History of recurrent or chronic infection
- Subject has had a splenectomy
- Subjects with a screening chest X-ray suggestive of TB without documentation of adequate TB treatment
- Any major surgical procedure within the 8 weeks before signing the consent form, or planning to undergo any such surgery within the 3 months after the last dose of study drug
- Clinically significant cardiovascular and/or cerebrovascular disease
- Predisposition to thromboembolic disease, or thromboembolic event (excluding superficial) in past 12 months
- Uncontrolled medical conditions: Significant concurrent, uncontrolled medical condition including, but not limited to renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral psychiatric disease, or evidence of demyelinating disease
- A 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
- Clinically significant abnormal laboratory values during the Screening period, other than those due to GO. Abnormal values are permitted if, upon re-test, the abnormality was resolved
- Unwillingness or inability to follow the procedures outlined in the protocol
- Mentally or legally incapacitated
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
GSK Investigational Site
Newcastle upon Tyne, NE1 3BZ
About this study
Official title: A Randomised, Comparator Controlled, Two Part, Open-label Study to Evaluate the Safety, Tolerability and Pharmacodynamics of Multiple Doses of Otelixizumab in Patients With Thyroid Orbitopathy
The purpose of this study is to investigate the safety and tolerability of otelixizumab in patients with Graves' ophthalmopathy (thyroid eye disease). There is currently no alternative therapy available for this condition other than treatment with steroids, or radiotherapy and surgery. The study also includes a comparison of the current steroid treatment, methylprednisolone, with the proposed new otelixizumab treatment.
Read the detailed description
This is a study of otelixizumab, a monoclonal antibody (MAb) directed against the human lymphocyte antigen CD3 (a protein found on a certain type of white blood cell). This will be an open-label, comparator-controlled, two part study to evaluate the safety and tolerability of otelixizumab in patients with Graves' ophthalmopathy (GO). It will also look to see if otelixizumab affects GO and how it works compared to methylprednisolone (the standard treatment for active GO).
In Part A, between one and four groups of 5 patients will receive doses of otelixizumab administered over 8 days. The first dose level will provide a low cumulative dose, this low dose level has been safely administered in previous studies. Safety and clinical response data will be reviewed after 8 weeks, if no clinical response is seen and there are no safety concerns, the dose of otelixizumab will be increased and a new group of subjects will enter Part A. In subsequent groups cumulative medium low, medium high, and high doses of otelixizumab may be investigated. However if a clinical response is seen at the lowest dose the study will move directly to Part B.
In Part B, patients will receive either otelixizumab at the dose set from Part A, over 8 days (5 patients) or methylprednisolone weekly for 12 weeks (5 patients). All dosing will be by intravenous infusion. All participants will undergo long term safety evaluation for 48 months.
Key assessments include vital signs, 12-lead ECG, liver function tests, thyroid function, viral monitoring, monitoring of cortisol and ACTH levels, laboratory safety tests and adverse event (side effect) data. Assessment of GO severity will be evaluated using recommended assessments including clinical activity assessments and quality of life questionnaires. Measurements of exploratory biomarkers (proteins found naturally in the blood) are also included in this study.
- Conditions
- Graves Ophthalmopathy
- Being tested
- Otelixizumab - low dose, Otelixizumab - medium low dose, Otelixizumab - medium high dose, Otelixizumab - high dose, Otelixizumab
- Keywords
- GSK2136525, Pharmacodynamics, Safety, Otelixizumab, Thyroid eye disease, Graves' ophthalmopathy, Repeat dose, Intravenous infusion, Tolerability, EUGOGO
- Medical subject headings
- Graves Ophthalmopathy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Otelixizumab - low doseDrug
8 day dose rising intravenous infusions of a low dose of otelixizumab
Otelixizumab - medium low doseDrug
8 day dose rising intravenous infusions of a medium low dose of otelixizumab
Otelixizumab - medium high doseDrug
8 day dose rising intravenous infusions of a medium high dose of otelixizumab
Otelixizumab - high doseDrug
8 day dose rising intravenous infusions of a high dose of otelixizumab
OtelixizumabDrug
8 day dose rising intravenous infusions of otelixizumab administered at a dose decided upon results from Part A.
Weekly intravenous infusions of methylprednisolone administered as 500 mg per week for 6 weeks and then 250 mg per week for 6 weeks
| Study group | Role | What they receive |
|---|---|---|
| Part A | Experimental | Up to 4 cohorts of 5 patients receive dose rising treatments of otelixizumab Receives: Drug: Otelixizumab - low dose; Drug: Otelixizumab - medium low dose; Drug: Otelixizumab - medium high dose; Drug: Otelixizumab - high dose |
| Part B - Otelixizumab | Experimental | Parallel dosing group in Part B receive otelixizumab over 8 days at a dose decided upon results from Part A Receives: Drug: Otelixizumab |
| Part B - Methylprednisolone | Active comparator | Parallel dosing group in Part B of weekly doses of methylprednisolone for 12 weeks Receives: Drug: Methylprednisolone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event
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.
Measured: Up to Month 24 (Long term follow-up)
Number of Participants With Laboratory Clinical Chemistry Abnormalities Meeting the Criteria for Potential Clinical Concern (PCC)
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.
Measured: Up to Month 24 (Long term follow-up)
Number of Participants With Laboratory Hematology Abnormalities Meeting the Criteria for PCC
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.
Measured: Upto Month 24 (Long term follow-up)
Number of Participants With Laboratory Urinalysis Abnormalities Meeting the Criteria for PCC
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.
Measured: Up to Month 24 (Long term follow-up)
Number of Participants With Thyroid Function Assessment, Hormone and Glucose Assay Abnormalities Meeting the Criteria for PCC
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.
Measured: Up to Week 24
Number of Participants With Vital Signs Abnormalities Meeting the Criteria for PCC
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.
Measured: Up to Month 24 (Long term follow-up)
Number of Participants With Electrocardiogram (ECG) Abnormalities Meeting the Criteria for PCC
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.
Measured: Screening (Day -35 to Day -1)
Number of Participants With an Epstein Barr Virus (EBV) Viral Load Abnormalities Meeting the Criteria for PCC
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.
Measured: Week 2 to Week 12
Individual Absolute Circulating Peripheral T Lymphocytes (T-cells), CD4+ and CD8+ Subset Counts
The lymphocyte subsets of T-cells, CD4+ and CD8+ cells were planned to be assessed at Day 1 (pre dose), Day 8 (pre dose), Week 2, Week 4, Week 8, Week 12 and Week 24. The absolute counts of the relevant lymphocyte subsets was to be determined by multiplying the percentages of the cell subsets with total lymphocyte counts. The percentages of relevant lymphocyte subsets was to be determined by flow cytometry. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Up to Week 24
Percentage of Circulating Peripheral T-cells, CD4+ and CD8+ Subset Counts
The lymphocyte subsets of T-cells, CD4+ and CD8+ cells were planned to be assessed at Day 1 (pre dose), Day 8 (pre dose), Week 2, Week 4, Week 8, Week 12 and Week 24. The percentages of relevant lymphocyte subsets was to be determined by flow cytometry. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Up to Week 24
Assessment of CD3/T-cell Receptor (TCR) Complex Saturation and Modulation
The assessment of CD3/TCR complex saturation and modulation was planned to be assessed on Day (1-8) pre dose, Week 2, Week 4, Week 8, Week 12 and Week 24. The extent of modulation was to be determined by the extent of TCR alpha beta (αβ) expression which was proportional to the combined levels of free CD3 sites and bound otelixizumab to CD4+ and CD8+ T cells. Bound levels of otelixizumab was planned to be determined by using flow cytometry method using an anti Immunoglobulin (Ig) antibody. The molecules of equivalent soluble fluorochrome (MESF) of the anti-Ig antibody was to be used to quantify the levels of bound otelixizumab present on T cells. Free otelixizumab binding sites (i.e., sites not occupied by otelixizumab administered to the participants) was to be detected by staining with fluorescein isothiocyanate (FITC) labelled otelixizumab. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Up to Week 24
Secondary outcomes (7)
Change From Baseline for Individual Scores at Week 12 Incorporated in the European Group on Graves' Orbitopathy (EUGOGO) Assessment Including, Eyelid Swelling, Clinical Activity Score (CAS) Score, Proptosis, Lid Width and Diplopia
The EUGOGO assessment of change was defined by improvement or deterioration of clinical scores. Improvement in EUGOGO was defined as improvement in two of the following measures in at least one eye, without deterioration in any of the same measures in both eyes: eyelid swelling according to color atlas evaluation, CAS by at least 2 points, proptosis by at least 2 millimeter (mm) by Hertel exophthalmometer, lid width by at least 2 mm, diplopia (disappearance or change in the degree) or improvement of >=8 degrees in motility unexplained by commensurate deterioration of motility of ipsilateral antagonists. Deterioration was defined by worsening by same quantity (as for improvement) of the same measures. Baseline was referred to assessment on Day 1 (pre dose). Change from Baseline was defined as post-Baseline value minus Baseline value. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Baseline (Day 1, pre dose) and Week 12
Change From Baseline for Participant-reported Health Related Quality of Life (QoL) Questionnaires of Short Form 36 ( SF-36) and Graves Ophthalmopathy (GO) QoL
Assessment of health related QoL was planned to be evaluated using the validated, disease specific, GO-QoL questionnaire and the SF-36 health survey questionnaire at Day 1 (pre dose) and Week 2- 24. Mean scores range from 0 (minimum) - 100 (maximum) with higher mean scores reflected better outcomes. Baseline was referred to assessment on Day 1 (pre dose). Change from Baseline was defined as post-Baseline value minus Baseline value. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Baseline (Day 1, pre dose) to Week 24
Change From Baseline Measurement of Orbital Volume as Measured by Computed Tomography (CT) Scan
The assessment of orbital volume measured by CT scan was planned to be assessed on Week 12 and Week 24. Baseline was referred to assessment at Screening. Change from Baseline was defined as post-Baseline value minus Baseline value. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Baseline (Screening), Week 12 and Week 24
Assessment of Anti-otelixizumab Antibodies
Anti-otelixizumab antibodies were planned to be assessed on Day 1 (pre dose), Day 8 (pre dose), Week 4-24 and Month 12. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Up to Month 12
Assessment of Circulating Cytokines of Interleukin 6 (IL6), IL10, Interferon Gamma (IFNγ) and Tumor Necrosis Factor Alpha (TNFα) up to 2 Weeks
Assessment of circulating cytokines of IL6, IL10, IFNγ and TNFα was planned to be assessed on Day 1-8 (pre dose) and Week 12. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Up to Week 2
Assessment of Exploratory Biomarkers
The exploratory biomarkers were planned to be assessed on Day 1 (pre dose), Week 4, Week 12 and Week 24. It included assessment of peripheral blood mononuclear cells (PBMC) markers, suppression assays for the measure of effector cell proliferation, quantification of effector memory T-cells subsets, autoreactivity assays using cytokine production of supernatants and CFSE dilution, cytokine production by in-vitro stimulated T-cells, circulating serum biomarkers and may include subsequently discovered biomarkers of the biological response associated with GO or medically related conditions and/or the action of otelixizumab. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Up to Week 24
Assessment of Exploratory Biomarkers of Ribonucleic Acid (RNA) Transcription Analysis of Peripheral Blood
The exploratory biomarkers of RNA transcription analysis of peripheral blood was planned to be assessed on Day 1(pre dose), Week 4 and Week 24. The assessment was to be done using microarray and RNA expression using quantitative reverse transcription polymerase chain reaction (RT-PCR). This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Measured: Up to Week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 May 2010 (estimated)
- Study start7 Jul 2010
- Primary completion29 Aug 2012
- Study completion29 Aug 2012
Why it stopped: Clinical study in Graves' ophthalmopathy terminated until there is a better understanding of an efficacious dose with Otelixizumab from other clinical studies.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Graves OphthalmopathyStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01114503
- Sponsor's protocol ID
- 112480
- Other IDs
- 2009-016747-19, 2009
- Status last verified
- Oct 2020
- First submitted
- 29 Apr 2010
- Last updated
- 30 Oct 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised, Comparator Controlled, Two Part, Open-label Study to Evaluate the Safety, Tolerability and Pharmacodynamics of Multiple Doses of Otelixizumab in Patients With Thyroid Orbitopathy
- ClinicalTrials.gov ID
- NCT01114503
- Acronym / sponsor ID
- 112480
- Conditions
- Graves Ophthalmopathy
- Keywords
- GSK2136525, Pharmacodynamics, Safety, Otelixizumab, Thyroid eye disease, Graves' ophthalmopathy, Repeat dose, Intravenous infusion
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Clinical study in Graves' ophthalmopathy terminated until there is a better understanding of an efficacious dose with Otelixizumab from other clinical studies.
- Enrolment
- 2 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- 7 Jul 2010 (actual)
- Primary completion
- 29 Aug 2012 (actual)
- Study completion
- 29 Aug 2012 (actual)
- First posted
- 3 May 2010 (estimated)
- Results
- Posted 3 Aug 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to investigate the safety and tolerability of otelixizumab in patients with Graves' ophthalmopathy (thyroid eye disease). There is currently no alternative therapy available for this condition other than treatment with steroids, or radiotherapy and surgery. The study also includes a comparison of the current steroid treatment, methylprednisolone, with the proposed new otelixizumab treatment.
Detailed description
This is a study of otelixizumab, a monoclonal antibody (MAb) directed against the human lymphocyte antigen CD3 (a protein found on a certain type of white blood cell). This will be an open-label, comparator-controlled, two part study to evaluate the safety and tolerability of otelixizumab in patients with Graves' ophthalmopathy (GO). It will also look to see if otelixizumab affects GO and how it works compared to methylprednisolone (the standard treatment for active GO).
In Part A, between one and four groups of 5 patients will receive doses of otelixizumab administered over 8 days. The first dose level will provide a low cumulative dose, this low dose level has been safely administered in previous studies. Safety and clinical response data will be reviewed after 8 weeks, if no clinical response is seen and there are no safety concerns, the dose of otelixizumab will be increased and a new group of subjects will enter Part A. In subsequent groups cumulative medium low, medium high, and high doses of otelixizumab may be investigated. However if a clinical response is seen at the lowest dose the study will move directly to Part B.
In Part B, patients will receive either otelixizumab at the dose set from Part A, over 8 days (5 patients) or methylprednisolone weekly for 12 weeks (5 patients). All dosing will be by intravenous infusion. All participants will undergo long term safety evaluation for 48 months.
Key assessments include vital signs, 12-lead ECG, liver function tests, thyroid function, viral monitoring, monitoring of cortisol and ACTH levels, laboratory safety tests and adverse event (side effect) data. Assessment of GO severity will be evaluated using recommended assessments including clinical activity assessments and quality of life questionnaires. Measurements of exploratory biomarkers (proteins found naturally in the blood) are also included in this study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Part A | Experimental | Drug: Otelixizumab - low dose, Drug: Otelixizumab - medium low dose, Drug: Otelixizumab - medium high dose, Drug: Otelixizumab - high doseUp to 4 cohorts of 5 patients receive dose rising treatments of otelixizumab |
| Part B - Otelixizumab | Experimental | Drug: OtelixizumabParallel dosing group in Part B receive otelixizumab over 8 days at a dose decided upon results from Part A |
| Part B - Methylprednisolone | Active comparator | Drug: MethylprednisoloneParallel dosing group in Part B of weekly doses of methylprednisolone for 12 weeks |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- Male or female between 18 and 75 years of age inclusive
- A female subject is eligible to participate if she is of:
- Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 mIU/ml and estradiol <40 pg/ml (<140 pmol/L) is confirmatory].
- Child-bearing potential and agrees to use one of the agreed contraception methods listed in the protocol for an appropriate period of time to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception for at least 2 weeks prior to dosing and for at least 6 months after the last dose.
- Male subjects must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until at least 60 days after the last dose.
Key exclusion criteria (30 listed)
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
- Positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines
- Positive test for HIV antibody
- Positive test for syphilis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Otelixizumab - low dose8 day dose rising intravenous infusions of a low dose of otelixizumab | Drug | Part A |
| Otelixizumab - medium low dose8 day dose rising intravenous infusions of a medium low dose of otelixizumab | Drug | Part A |
| Otelixizumab - medium high dose8 day dose rising intravenous infusions of a medium high dose of otelixizumab | Drug | Part A |
| Otelixizumab - high dose8 day dose rising intravenous infusions of a high dose of otelixizumab | Drug | Part A |
| Otelixizumab8 day dose rising intravenous infusions of otelixizumab administered at a dose decided upon results from Part A. | Drug | Part B - Otelixizumab |
| MethylprednisoloneWeekly intravenous infusions of methylprednisolone administered as 500 mg per week for 6 weeks and then 250 mg per week for 6 weeks | Drug | Part B - Methylprednisolone |
Primary outcome
Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event
Time frame: Up to Month 24 (Long term follow-up)
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.
Number of Participants With Laboratory Clinical Chemistry Abnormalities Meeting the Criteria for Potential Clinical Concern (PCC)
Time frame: Up to Month 24 (Long term follow-up)
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.
Number of Participants With Laboratory Hematology Abnormalities Meeting the Criteria for PCC
Time frame: Upto Month 24 (Long term follow-up)
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.
Number of Participants With Laboratory Urinalysis Abnormalities Meeting the Criteria for PCC
Time frame: Up to Month 24 (Long term follow-up)
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.
Number of Participants With Thyroid Function Assessment, Hormone and Glucose Assay Abnormalities Meeting the Criteria for PCC
Time frame: Up to Week 24
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.
Number of Participants With Vital Signs Abnormalities Meeting the Criteria for PCC
Time frame: Up to Month 24 (Long term follow-up)
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.
Number of Participants With Electrocardiogram (ECG) Abnormalities Meeting the Criteria for PCC
Time frame: Screening (Day -35 to Day -1)
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.
Number of Participants With an Epstein Barr Virus (EBV) Viral Load Abnormalities Meeting the Criteria for PCC
Time frame: Week 2 to Week 12
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.
Individual Absolute Circulating Peripheral T Lymphocytes (T-cells), CD4+ and CD8+ Subset Counts
Time frame: Up to Week 24
The lymphocyte subsets of T-cells, CD4+ and CD8+ cells were planned to be assessed at Day 1 (pre dose), Day 8 (pre dose), Week 2, Week 4, Week 8, Week 12 and Week 24. The absolute counts of the relevant lymphocyte subsets was to be determined by multiplying the percentages of the cell subsets with total lymphocyte counts. The percentages of relevant lymphocyte subsets was to be determined by flow cytometry. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Percentage of Circulating Peripheral T-cells, CD4+ and CD8+ Subset Counts
Time frame: Up to Week 24
The lymphocyte subsets of T-cells, CD4+ and CD8+ cells were planned to be assessed at Day 1 (pre dose), Day 8 (pre dose), Week 2, Week 4, Week 8, Week 12 and Week 24. The percentages of relevant lymphocyte subsets was to be determined by flow cytometry. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
Assessment of CD3/T-cell Receptor (TCR) Complex Saturation and Modulation
Time frame: Up to Week 24
The assessment of CD3/TCR complex saturation and modulation was planned to be assessed on Day (1-8) pre dose, Week 2, Week 4, Week 8, Week 12 and Week 24. The extent of modulation was to be determined by the extent of TCR alpha beta (αβ) expression which was proportional to the combined levels of free CD3 sites and bound otelixizumab to CD4+ and CD8+ T cells. Bound levels of otelixizumab was planned to be determined by using flow cytometry method using an anti Immunoglobulin (Ig) antibody. The molecules of equivalent soluble fluorochrome (MESF) of the anti-Ig antibody was to be used to quantify the levels of bound otelixizumab present on T cells. Free otelixizumab binding sites (i.e., sites not occupied by otelixizumab administered to the participants) was to be detected by staining with fluorescein isothiocyanate (FITC) labelled otelixizumab. This endpoint was not analyzed due to the early termination of the study and since only 2 participants were recruited.
7 secondary outcomes
Change From Baseline for Individual Scores at Week 12 Incorporated in the European Group on Graves' Orbitopathy (EUGOGO) Assessment Including, Eyelid Swelling, Clinical Activity Score (CAS) Score, Proptosis, Lid Width and Diplopia
Time frame: Baseline (Day 1, pre dose) and Week 12
Change From Baseline for Participant-reported Health Related Quality of Life (QoL) Questionnaires of Short Form 36 ( SF-36) and Graves Ophthalmopathy (GO) QoL
Time frame: Baseline (Day 1, pre dose) to Week 24
Change From Baseline Measurement of Orbital Volume as Measured by Computed Tomography (CT) Scan
Time frame: Baseline (Screening), Week 12 and Week 24
Assessment of Anti-otelixizumab Antibodies
Time frame: Up to Month 12
Assessment of Circulating Cytokines of Interleukin 6 (IL6), IL10, Interferon Gamma (IFNγ) and Tumor Necrosis Factor Alpha (TNFα) up to 2 Weeks
Time frame: Up to Week 2
Assessment of Exploratory Biomarkers
Time frame: Up to Week 24
Assessment of Exploratory Biomarkers of Ribonucleic Acid (RNA) Transcription Analysis of Peripheral Blood
Time frame: Up to Week 24
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Oct 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Otelixizumab - low dose, Otelixizumab - medium low dose and Otelixizumab - medium high dose in people with Graves Ophthalmopathy, run by GlaxoSmithKline at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 30 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Aug 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event (time frame: Up to Month 24 (Long term follow-up)). The study lists 11 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2020.