Clinical Trial Results:
A phase II trial of Tocilizumab in anti-TNF refractory patients with JIA associated uveitis.
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Summary
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EudraCT number |
2015-001323-23 |
Trial protocol |
GB |
Global end of trial date |
28 Sep 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Oct 2019
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First version publication date |
05 Oct 2019
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Other versions |
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Summary report(s) |
Baseline characteristics |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CH/2013/4247
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Additional study identifiers
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ISRCTN number |
ISRCTN95363507 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
AR UK ref: 20659 | ||
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Sponsors
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Sponsor organisation name |
University Hospitals Bristol NHS Foundation Trust
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Sponsor organisation address |
Upper Maudlin Street, Bristol, United Kingdom, BS2 8AE
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Public contact |
Ashley Jones, Liverpool Clinical Trials Statistician, Medicines for Children Clinical Trials Unit, Clinical Trials Research Centre, +44 1517958787, lctcqa@liverpool.ac.uk
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Scientific contact |
Ashley Jones, Liverpool Clinical Trials Statistician, Medicines for Children Clinical Trials Unit, Clinical Trials Research Centre, +44 1517958787, lctcqa@liverpool.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
22 Mar 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Jun 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Sep 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this trial is to estimate the clinical response rate of uveitis to Tocilizumab in combination with MTX in children with JIA-associated uveitis who have failed anti-TNF therapy, and to determine whether further research into the use of this intervention for the treatment of anti-TNF refractory JIA-associated uveitis should be conducted.
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Protection of trial subjects |
The first dose of IMP was administered by the research / clinical team looking after the patient. All participants or a family member were invited to self administer the study treatment after the first dose and taught as such to do this under procedures in place within each participating centre for teaching this. The first dose they administered was also be under supervision of the clinical team, who ensured they are confident and able to carry out all parts of the procedure appropriately and accurately. This would allow patients to then have their remaining trial treatment in the familiar surroundings of their home to reduce distress. If they did not want to do this, then arrangements were put in place on an individual basis for ensuring trial medication is administered as prescribed.
Study visits and study assessments were set around routine clinical care to minimise the inconvenience for patients and families, travel expenses were provided for visits outside of routine care that were specific for APITUDE.
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Background therapy |
All subjects to receive a stable dose of methotrexate. | ||
Evidence for comparator |
Tocilizumab (trade name RoActemra) is also a biological therapy blocking the action of interleukin (IL)-6. In arthritis, IL-6 causes tiredness, anaemia, and inflammation and damage to bones, cartilage and tissue. Tocilizumab reduces these effects. Previous studies looking at the effect of Tocilizumab in children have been conducted looking at Rheumatology examinations only. However trial of Tocilizumab in children with the systemic form of JIA have responded dramatically to this treatment in a short time span and became the first drug licenced for use in JIA in fifty years, obtaining NICE approval for this indication. It is also being trialled at present in polyarticular forms of JIA with good effect. However these clinical trials for Tocilizumab state that a diagnosis of Uveitis is part of the exclusion criteria. | ||
Actual start date of recruitment |
04 Nov 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 21
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Worldwide total number of subjects |
21
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EEA total number of subjects |
21
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
8
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Adolescents (12-17 years) |
13
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial took place in 7 United Kingdom centres. | ||||||
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Pre-assignment
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Screening details |
There was a total of 58 screenings assessed for eligibility. 22 were eligible and consented, one patient was immediately found to be ineligible and was therefore withdrawn from the study. | ||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Tocilizumab | ||||||
Arm description |
2-3 weekly injections of Tocilizumab with Methotrexate. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Tocilizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Patients received Tocilizumab dosed according to body weight (BW):
Patients weighing ≥ 30 kg dosed with 162 mg of Tocilizumab every two weeks
Patients weighing < 30 kg dosed with 162 mg of Tocilizumab every three weeks
Tocilizumab was supplied in a single use pre-filled syringe fitted into a needle safety device. After removing the pre-filled syringe from the refrigerator the pre-filled syringe was allowed to reach room temperature (18°C to 28C°) by waiting for 25 to 30 minutes, before injecting Tocilizumab. The syringe should not be shaken. After removing the cap the injection must be started within five minutes, to prevent the medicine from drying out and blocking the needle. If the pre-filled syringe was not used within five minutes of removing the cap, it must be disposed of in a puncture resistant container and then a new pre-filled syringe should be used.
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Baseline characteristics reporting groups
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Reporting group title |
Overall
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Reporting group description |
2-3 weekly injections of Tocilizumab in combination with Methotrexate. The dosage was calculated based on patient body weight. Response to treatment was assessed after 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
2-3 weekly injections of Tocilizumab with Methotrexate. | ||
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End point title |
Treatment response [1] | ||||||||||
End point description |
Response to treatment is defined as per SUN criteria as a 2 step decrease in the level of inflammation (anterior chamber cells) or decrease to zero between baseline (prior to trial treatment initiation) and after 12 weeks of treatment.
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End point type |
Primary
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End point timeframe |
Patients were assessed for treatment response after 12 weeks of treatment.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analyses have been added as a supplementary document. |
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Attachments |
Untitled (Filename: Treatment response.pdf) |
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| Notes [2] - One patient was excluded straight after registration |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Total oral corticosteorid dose - treatment period | ||||||||
End point description |
The total dose is calculated by summing the daily doses and standardised to per patient years.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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| Notes [3] - There were only 4 patients on oral steroids at the beginning of the study |
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| No statistical analyses for this end point | |||||||||
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End point title |
Reduction in topical corticosteroids from entry dose: Time to reduction to < 2 drops - treatment period | ||||||||||
End point description |
Reduction in topical corticosteroids from entry dose will be analysed for a subset of patients. Time to reduction to < 2 drops for those patients already on > = 2 drops at registration.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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| No statistical analyses for this end point | |||||||||||
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End point title |
Reduction in topical corticosteroids from entry dose: Time to reduction to 0 drops - treatment period | ||||||||||
End point description |
Reduction in topical corticosteroids from entry dose will be analysed from a subset of patients. Time to reduction to 0 drops for those patients already on > = 0 drops at registration.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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| No statistical analyses for this end point | |||||||||||
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End point title |
Total oral corticosteroid dose -treatment period and follow up | ||||||||
End point description |
The total dose is calculated by summing the daily doses and standardised to per patient years.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration until the end of trial.
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| Notes [4] - There were 21 patients registered and 6 received oral corticosteroids |
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| No statistical analyses for this end point | |||||||||
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End point title |
Reduction in topical corticosteroids from entry dose: Time to reduction to < 2 drops - treatment period and follow up | ||||||||||
End point description |
Reduction in in topical cortical corticosteroids from entry dose to < 2 drops will be analysed for a subset of patients. Time to reduction to < 2 drops for those patients already on > = 2 drop.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration until the end of trial.
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| No statistical analyses for this end point | |||||||||||
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End point title |
Reduction in topical corticosteroids from entry dose: Time to reduction to 0 drops - treatment period and follow up | ||||||||||
End point description |
Reduction in corticosteroids from entry dose to 0 drops will be analysed for a subset of patients. Time to reduction to 0 drops for those patients already on > = 0 drops.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration until the end of trial.
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| No statistical analyses for this end point | |||||||||||
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End point title |
Optic and Ocular: Visual acuity measured by age-appropriate LogMAR assessment | ||||||||||||||||||||||||||||||||||||
End point description |
Statistical analyses have been added as a supplementary document
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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Attachments |
Untitled (Filename: joint modelling logmar.pdf) |
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| Notes [5] - 21 at baseline, 20 at 4 weeks, 19 at 8 weeks, 15 at 12 weeks, 6 at 16 weeks, 6 at 20 weeks, 4 at 24. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Optic and Ocular: Number of participants with resolution of associated optic nerve | ||||||
End point description |
Assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) where available.
No participants who had optic nerve were eligible in both eyes and therefore the analysis for resolution in both eyes was not possible.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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| No statistical analyses for this end point | |||||||
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End point title |
Optic and Ocular: Number of participants with resolution of associated macular oedema | ||||||
End point description |
No participants who had macular oedema were eligible in both eyes and therefore the analysis for resolution in both eyes was not possible.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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| No statistical analyses for this end point | |||||||
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End point title |
Optic and Ocular: Number of participants with disease control at 12 weeks | ||||||||||
End point description |
Disease control is defined as zero cells, with treatment for 12 weeks.
Two analyses were performed for this outcome: disease control in at least 1 eye, and disease control in both eyes.
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End point type |
Secondary
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End point timeframe |
Assessed from registration until:
- time of no response
- completion of 6 months of treatment
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| No statistical analyses for this end point | |||||||||||
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End point title |
Optic and Ocular: Number of participants with disease control at 24 weeks | ||||||||||
End point description |
Disease control is defined as zero cells, with treatment for 24 weeks
Two analyses were performed for this outcome: disease control in at least 1 eye, and disease control in both eyes.
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End point type |
Secondary
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End point timeframe |
Assessed from registration until:
- time of no response
- completion of 6 months of treatment
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| No statistical analyses for this end point | |||||||||||
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End point title |
Optic and Ocular: Number of participants entering disease remission at 12 weeks | ||||||||||
End point description |
Disease remission is defined as zero cells without treatment for 12 weeks.
Two analyses were performed for this outcome: disease remission in at least 1 eye, and disease remission in both eyes.
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End point type |
Secondary
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End point timeframe |
Assessed from registration until:
- time of no response
- completion of 6 months of treatment
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| No statistical analyses for this end point | |||||||||||
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End point title |
Optic and ocular: Number of participants entering disease remission at 24 weeks | ||||||||||
End point description |
Disease remission is defined as zero cells without treatment for 24 weeks.
two analyses were performed for this outcome: disease remission in at least 1 eye. and disease remission in both eyes.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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| No statistical analyses for this end point | |||||||||||
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End point title |
Optic and Ocular: Duration of sustaining inactive disease | ||||||||
End point description |
Duration of sustaining inactive disease (zero cells, with or without topical treatment)
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End point type |
Secondary
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End point timeframe |
Assessed from registration until:
- time of no response
- completion of 6 months of treatment
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| No statistical analyses for this end point | |||||||||
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End point title |
Optic and ocular: Failure to reduce eye drops to 2 drops/day by or at 12 weeks | ||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to the 12 weeks visit
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| No statistical analyses for this end point | |||||||
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End point title |
Quality of life assessments: Childhood Health Questionnaire (CHQ) | ||||||||||||||||||||||||||||||||||||
End point description |
The CHQ consists of two scores:
Physical score (PhS)
Psychosocial score (PsS)
Statistical analyses have been added as a supplementary document
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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Attachments |
chq |
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| Notes [6] - 20 at baseline & 4 weeks, 18 at 8, 4 at 12, 6 at 16, 6 at 20, 4 at 24. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Quality of life assessments: Childhood Health Assessment Questionnaire (CHAQ) | ||||||||||||||||||||||
End point description |
Statistical analyses have been added as a supplementary document
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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Attachments |
Untitled (Filename: Childhood Health Assessment Questionnaire.pdf) |
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| Notes [7] - 21 at baseline & 4 weeks, 19 at 8, 15 at 12, 6 at 16, 6 at 20, 4 at 24 |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
American College of Rheaumatology (ACR) score | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The 6 paediatric core set criteria assessed at each study visit are:
Physician global assessment of disease activity (10 cm visual analogue scale).
Parent/patient assessment of overall well-being (10 cm visual analogue scale).
Functional ability (Childhood Health Assessment Questionnaire, CHAQ).
Number of joints with active arthritis.
Number of joints with limited range of movement.
Erythrocyte sedimentation rate.
The ACR Paediatric 30, 50, 70, 90 and 100 levels are defined as 30%, 50%, 70%, 90% and 100%
improvement, respectively, in a minimum of three variables in the core set with worsening of one
variable by no more than 30% as defined in the ACR criteria.
The frequencies below show the number of participants who achieved each ACR level.
Statistical analyses have been added as a supplementary document.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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Attachments |
Untitled (Filename: ACR.pdf) |
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| Notes [8] - See supplementary table for the number of patients who had missing data |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of participants requiring change in biologic /disease-modifying anti-rheumatic drugs (DMARDS) therapy due to disease flare of their arthritis or failure to response to treatment of arthritis | ||||||
End point description |
DMARDs are disease-modifying anti-rheumatic drugs.
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End point type |
Secondary
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End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
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| No statistical analyses for this end point | |||||||
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End point title |
Number of participants undergoing flare of arthritis | ||||||||||
End point description |
The definition of 'disease flare' is a worsening of 30% or more of the 6 variables of the JIA core set, with no more than one variable improving by 30% or more.
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End point type |
Secondary
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End point timeframe |
Assessed from registration until:
- time of no response
- completion of 6 months of treatment
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of participants in remission on and off medication of their JIA | ||||||||||
End point description |
Clinical remission of JIA whilst on medication is defined as per Wallace (2004):
• The criteria for inactive disease must be met for a minimum of 6 continuous months while the patient is on (anti-rheumatic, anti-inflammatory* and anti-uveitis) medication in order for the patient to be considered to be in a state of clinical remission on medication.
Clinical remission of JIA whilst off medication is defined as per Wallace (2004):
• The criteria for inactive disease (see definition in section 17.4.9.2 above) must be met for a minimum of 12 continuous months while off all anti-rheumatic, anti-inflammatory* and anti-uveitis medications in order for the patient to be considered to be in a state of clinical remission off medication.
Patients will not be able to assessed for inactive disease for a minimum of 12 months with the treatment phase being 6 months and the follow-up phase being 1 month so clinical remission of JIA whilst off medication is unable to be analysed.
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End point type |
Secondary
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End point timeframe |
Throughout the duration of the study
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| No statistical analyses for this end point | |||||||||||
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End point title |
Juvenile Arthritis Disease Activity Score (JADAS) | ||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Juvenile Arthritis Disease Activity Score (JADAS) is comprised of four components:
• physician global assessment of disease activity,
• parent/patient global assessment of well-being,
• active joint count, in 27, 71 or 10 joints,
• erythrocyte sedimentation rate (ESR).
The JADAS is calculated as a sum of scores from its four components detailed below, giving global scores of 0-57, 0-101 and 0-40 for the JADAS-27, JADAS-71 and JADAS-10 respectively.
Statistical analyses have been added as a supplementary document
|
||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
|
||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
Attachments |
Juvenile Arthritis Disease Activity Score |
||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||
End point title |
Laboratory parameters | ||||||
End point description |
The parameters reported on for haematological assessments are:
-Heamatocrit
-Haemoglobin
-Red blood cell count
-White blood cell count
-Neutrophils
-Lymphocytes
-Monocytes
-Basophils
-Eosinophils
-Platelet count
-Erythrocyte sedimentation rate
-Plasma viscosity (only done if ESR not available
The parameters reported on for biochemical assessments are:
-C- Reactive protein (CRP)
-Urea
-Creatinine
-Sodium
-Potassium
-Calcium
-Inorganic phosphate
-Glucose
-Chloride
-Bicarbonate
-Total bilirubin
-LDL
-HDL
-Triglycerides
-Total cholesterol
-Alanine aminotransferase (ALT)
-Aspartate aminotransferase (AST)
The parameters reported on for urinalysis are:
-Protein
-Glucose
-Blood
-Leukocyte esterase
-Specific gravity
-pH
Supplementary tables summarising the data have been uploaded.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Throughout the duration of the study.
|
||||||
|
|||||||
Attachments |
Laboratory Parameters |
||||||
| No statistical analyses for this end point | |||||||
|
|||||||||
End point title |
Compliance according to participnat diaries | ||||||||
End point description |
Treatment diaries were used to estimate participant compliance. No formal statistical analysis was undertaken.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||
End point title |
Reduction in systemic corticosteroid dose from entry dose to 0mg - treatment period | ||||||||||
End point description |
Reduction in systemic corticosteroid dose from entry dose to 0mg will be analysed for a subset of patients, as not everyone will be taking systemic corticosteroids at registration.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||
End point title |
Reduction in systemic corticosteroid dose from entry dose to <5mg - treatment period | ||||||||||
End point description |
Reduction in systemic corticosteroid dose from entry dose to <5mg will be analysed for a subset of patients, as not everyone will be taking systemic corticosteroids at registration.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||
End point title |
Rate of systemic corticosteroid dose from entry dose - treatment period | ||||||||
End point description |
The total dose is calculated by summing the daily doses and standardised to per patient years.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||
End point title |
Reduction in systemic corticosteroid dose from entry dose to 0mg - treatment period and follow up | ||||||||||
End point description |
Reduction in systemic corticosteroid dose from entry dose to 0mg will be analysed for a subset of patients, as not everyone will be taking systemic corticosteroids at registration.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
From registration until the end of study.
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||
End point title |
Reduction in systemic corticosteroid dose from entry dose to <5mg - treatment period and follow up | ||||||||||
End point description |
Reduction in systemic corticosteroid dose from entry dose to <5mg will be analysed for a subset of patients, as not everyone will be taking systemic corticosteroids at registration.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||
End point title |
Rate of systemic corticosteroid dose from entry dose - treatment period | ||||||||
End point description |
|||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Participants were assessed from registration up until:
- withdrawal
-time of 'no response'
- completion of treatment,
whichever came first
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
|
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Timeframe for reporting adverse events |
Adverse events were collected up to 30 days following treatment cessation.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
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Reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
28 Aug 2015 |
The first amendment to the protocol updated the number of centres to 6 and corrected the schematic of study design to show that patients who respond to treatment at 3 months complete the treatment period and do not cease trial treatment at 12 week. ILAR diagnostic criteria from inclusion criteria 1 was merged with exclusion criteria 1. Clarification of definition of active anterior uveitis added to inclusion criteria 2 and inclusion criteria's 4 and 5 merged into one criteria. Previous registration added as an exclusion, exclusion criteria updated to state that patients on oral anti-glaucoma therapy are excluded, clarification added to exclusion criteria stating that patients need to be on stable eye drops for 1 week prior to screening, untreated latent TB criteria from exclusion 14 added to exclusion 15, exclusion criteria 29 removed as it is covered in exclusion criteria 28 (immunization with live/attenuated vaccine) and exclusion criteria added excluded patient who have had joint injections with 4 weeks prior to registration. Method of registering patients amended to instruct sites to register patients via an online registration system. References to SmPC replace with IB. Text added stating that patients who have an increase in weight over 30kg or decrease in weight to less than 30kg should switch dosing regimen, text added giving guidance for interrupting trial treatment and text added giving guidance on discontinuing trial treatment. Text added to confirm that patients should receive trial injections up to and including week 24, medications permitted updated to confirm that patients need to be on stable dose of eye drops 1 week prior to screening, and medications not permitted updated to include Systemic treatment with acetazolamide is not allowed. |
||
28 Aug 2015 |
(Continued) Table of assessment updated to clarify which assessments are done at screening and which are done at registration. Information added confirming that interim analysis is carried out after 10 patients have been recruited. Adverse event of special interest list updated in line with AESI guidance from Roche and appendix added giving guidance for liver function tests. |
||
05 Nov 2015 |
The second amendment updated trial management and monitoring details, added a secondary outcome to develop a fully consented trial related Bio bank for subsequent investigation and an amendment to minimum time needed between visits to assessing response to trial treatment. |
||
11 Jan 2016 |
The third amendment to the protocol updated the OCT section to that macular foveal thicknes results will be collected. |
||
14 Jul 2016 |
The fourth amendment to the protocol added JADAS as a secondary endpoint. Text added instructing sites to contact trial co-ordinator for any queries relating to reduction of MTX. Text added to state that ANA, dsDNA and ENA test should be conducted if patients stop treatment or withdraw before week 24. Text added to state that ANA, dsDNA and ENA test should be conducted if patients stop treatment or withdraw before 24. Text amended to reflect that local investigators assess relationship and seriousness of adverse events only. Contact details for reporting serious adverse events updated. |
||
31 May 2017 |
The fifth amendment to the protocol updated trial telephone and fax details. White blood cell (WBC) count criteria amended to 4,000/mm3 (<4.0 x 109/L), platelet count added in 10^9/L to correspond with CRFs and neutrophil count amended to <2,000/mm3 (<2.0 x 109/L). Text were added to state that full eligibility must be confirmed by a doctor on the delegation log and to state that a patient may only be registered once full eligibility has been confirmed. Total Bilirubinin μmol added to correspond with CRF, as well as, neutrophil count in x10^9/L, and platelet count in x10^9/L. Guidance adding for discontinuing treatment for the trial and non-trial eye, medication allowed in the non-trial eye, and medication not allowed in the non-trial eye. Fax number for reporting SAEs updated and clarification to time point for reporting SAEs. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
