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Trial registered on ANZCTR


Registration number
ACTRN12613001027707
Ethics application status
Approved
Date submitted
11/09/2013
Date registered
16/09/2013
Date last updated
23/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Alemtuzumab in Multiple Sclerosis Safety System development
Scientific title
Developing systems to minimise the risk of multiple sclerosis (MS) treatment with alemtuzumab
Secondary ID [1] 283202 0
Nil
Universal Trial Number (UTN)
U1111-1147-9190
Trial acronym
AMS3
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Sclerosis 290062 0
Condition category
Condition code
Neurological 290439 290439 0 0
Multiple sclerosis

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
2
Target follow-up type
Years
Description of intervention(s) / exposure
A two year observational study of open label treatment with alemtuzumab for multiple sclerosis (MS). The aim of the study is to develop efficient information-technology (IT) based methods for the monthly monitoring required by the risk management protocols after treatment with alemtuzumab. The effectiveness of alemtuzumab in MS has already been demonstrated in randomised trials and is not the subject of this study.

Normally after treatment of MS with alemtuzumab patients are required to have ongoing monthly pathology monitoring. The study is to test the successful development of an electronic semi-automated monitoring of pathology results. There is no additional involvement for participants other than the normal monthly pathology testing per alemtuzumab treatment protocol.
Intervention code [1] 287926 0
Not applicable
Comparator / control treatment
Open label treatment with alemtuzumab per CAREMS1 protocol, no control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 290465 0
Successful development of an IT architecture to monitor monthly pathology results electronically after treatment of MS patients with alemtuzumab.

The success will be measured by whether the package works, including integration between pathology company results and our fetching programme and interrogation of the data remotely and generation of remote alerts.
Timepoint [1] 290465 0
One year from commencement
Secondary outcome [1] 304561 0
The secondary endpoints are to measure the role of the pre treatment safety screen and to measure the functional capacity of PRIME.

Treatment and safety data will be collected but are not endpoints of this study.

Time and cost for alemtuzumab risk management protocol (RMP) vs immunosuppressionscreen (data progressively accrued, available at time of last patient enrolled). Measure = cost per patient for RMP vs immunosuppression screen.

Timepoint [1] 304561 0
Two years from commencement
Secondary outcome [2] 304615 0
Additional risks identified with immunosuppression screen (data progressively accrued, available at time of last patient enrolled). Measure = elaborate on specific risks

Timepoint [2] 304615 0
Two years
Secondary outcome [3] 304616 0
Centralise all appropriately coded alemtuzumab study results in a single web browser (Webster). Measure = yes / no

Timepoint [3] 304616 0
Two years
Secondary outcome [4] 304617 0
Development of a functioning automated system. Measure = yes / no

Timepoint [4] 304617 0
Two years
Secondary outcome [5] 304618 0
Testing of a system with dummy results. Measure = yes / no

Timepoint [5] 304618 0
Two years
Secondary outcome [6] 304619 0
Testing of a system with real world results from patients anywhere in the state of NSW, Australia. Measure = yes / no

Timepoint [6] 304619 0
Two years
Secondary outcome [7] 304620 0
Monitoring of tests: 95% of results reviewed by automated system once operational to end 24 months. Measure = yes / no

Timepoint [7] 304620 0
Two years
Secondary outcome [8] 304621 0
Flags for deviation from results window or results parameters - 95% generated by automated system once operational to end June 2014. Measure = yes / no

Timepoint [8] 304621 0
Two years
Secondary outcome [9] 304622 0
Human factors integration: were there results or lack thereof that could not be finalized within 7 calendar days due to human factors (i.e. nurse not acting on results, inability to communicate with doctor or patient; patient not complying with need for test etc). Measure = yes / no

Timepoint [9] 304622 0
Two years

Eligibility
Key inclusion criteria
1. Willing to provide informed consent to both treatment with alemtuzumab and inclusion in the PRIME clinical decision support system monitoring procedures
2. Age 18 or older as of the date the consent is signed
3. Definite relapsing remitting MS by McDonald 2010 criteria
4. Cranial MRI scan demonstrating white matter lesions attributable to MS within 1 year of Screening
5. Active MS as signified by at least 2 relapses in the last 2 years and at least 1 relapse in the last 1 year
6. Either:
a. Failure of first line disease-modifying treatment as determined by: at least 1 relapse of MS despite treatment with a TGA-approved treatment for MS (interferons, glatiramer, teriflunomide, fingolimod or natalizumab), or at least 1 relapse in a patient unable to be treated with TGA-approved MS treatments due to intolerance or unacceptable risks of these treatments
b. Previously untreated MS that is associated with at least one gadolinium enhancing lesion on MRI in the last 1 year.
7. Diagnosed disease duration <= 10years
8. Baseline EDSS 0 – 4.0
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a. As per CAMMS03409 amendment 2:
i. Does not wish to receive alemtuzumab
ii. Ongoing participation in any other investigational study
iii. Has received alemtuzumab off-label
iv. Known bleeding disorder (eg, dysfibrinogenemia, factor IX deficiency, hemophilia, Von Willebrand's disease, Disseminated Intravascular Coagulation [DIC], fibrinogen deficiency, or other clotting factor deficiency) or therapeutic anticoagulation
v. Diagnosis of immune thrombocytopenic purpura (ITP), or other autoimmune hematologic abnormality.
vi. History of malignancy, except basal cell skin carcinoma
vii. Intolerance of pulsed corticosteroids, especially a history of steroid psychosis
viii. Significant non-MS autoimmune disease including but not limited to: immune cytopenias, rheumatoid arthritis, systemic lupus erythematosus, other connective tissue disorders, vasculitis, inflammatory bowel disease, severe psoriasis, or anti-glomerular basement membrane disease (anti-GBM disease, also known as Goodpasture’s disease)
ix. Major psychiatric disorder or epileptic seizures not adequately controlled by treatment
x. Known infection with hepatitis B or C virus, seropositivity for human immunodeficiency virus (HIV).
xi. History of invasive fungal infections
xii. Unwilling to agree to use a reliable and acceptable contraceptive method for at least 6 months following each alemtuzumab treatment cycle (fertile patients only). Reliable and effective contraceptive method(s) include: intrauterine device (IUD), hormonal-based contraception, surgical sterilization, abstinence or double-barrier contraception (condom and occlusive cap [diaphragm or cervical cap with spermicide])
b. Plus (local exclusion criteria)
i. Not resident in NSW
ii. Not able to access Douglass Hanly Moir pathology services
iii. Not able or likely to fulfil the requirements of the study for any other reason
iv. Not able to access electronic reminders and alerts (patient must have both a mobile (cell) phone and a valid regularly checked email address, the patient’s designate person must have at least one of these two methods of contact, prefer both)
v. Allergic or intolerant of any agent required for the completion of this study (i.e alemtuzumab, gadolinium contrast)
vi. No history of primary infection or vaccination with varicella zoster virus, until vaccinated
vii. Other significant active or latent infection until treated
viii. Any other reason that an investigator regards as a contraindication to entering or ability to complete the study
c. The following are not exclusion criteria but caution should be exercised in including patients with these criteria noting that these were exclusion criteria for the alemtuzumab RCTs
i. Prior exposure to natalizumab, fingolimod, mitoxantrone, azathioprine, cladribine, cyclophosphamide, cyclosporine A, methotrexate, or any other immunosuppressive agent
ii. Patients > 50 years of age
iii. Disease duration 5-10 years after diagnosis
iv. EDSS 3.5-4
v. Patients with known thyroid autoimmunity or thyroid antibodies. Such patients are highly likely to develop clinical thyroid autoimmunity and this should be discussed with the patient.

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Statistical methods

As this is a development study rather than a drug trial there are no complex statistical requirements arising and no planned analyses other than simple summary statistics for performance of PRIME.

Where required the statistical assistance of the Concord hospital liaison statistician shall be used, using SPSS or graphpad as appropriate.

Summary statistics will be computed and displayed by treatment group and scheduled assessment time. Summary statistics for continuous variables will minimally include n, mean, standard deviation, minimum, median, and maximum. For categorical variables, frequencies and percentages will be presented. Graphical displays will be provided as appropriate.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 1506 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 7346 0
2139 - Concord Repatriation Hospital

Funding & Sponsors
Funding source category [1] 287944 0
Commercial sector/Industry
Name [1] 287944 0
Genzyme Sanofi
Address [1] 287944 0
Building D, 12-24 Talavera Road, Macquarie Park NSW 2113 AUSTRALIA
Locked Bag 2227, North Ryde BC NSW 1670 AUSTRALIA
Country [1] 287944 0
Australia
Primary sponsor type
Hospital
Name
Sydney Local Health District
Address
1 Hospital Rd
Concord Hospital
NSW 2139
Country
Australia
Secondary sponsor category [1] 286662 0
None
Name [1] 286662 0
Address [1] 286662 0
Country [1] 286662 0
Other collaborator category [1] 277612 0
Commercial sector/Industry
Name [1] 277612 0
Medical Safety Systems
Address [1] 277612 0
4/94 Mallett St
Camperdown NSW 2050
Country [1] 277612 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289872 0
Concord Repatriation General Hospital
Ethics committee address [1] 289872 0
1 Hospital Rd
Concord Hospital
NSW 2139
Ethics committee country [1] 289872 0
Australia
Date submitted for ethics approval [1] 289872 0
01/10/2013
Approval date [1] 289872 0
24/01/2014
Ethics approval number [1] 289872 0
HREC/13/CRGH/256 CH62/6/2013- 180 – S Reddel Alemtuzumab Medical Safety Systems Study (AMS3) Developing systems to minimise the risk of MS treatment with alemtuzumab

Summary
Brief summary
Executive Summary

Alemtuzumab is a highly effective treatment for multiple sclerosis which has been demonstrated by three major clinical trials. However there are significant safety concerns arising from both the nature of the treatment and the results of the clinical trials.

The principal risk is the late development of other treatable autoimmune diseases, such as immune thrombocytopenia. It is likely that by monitoring treated patients with regular blood tests, including monthly platelet counts, patients who develop such autoimmune diseases can be identified and potentially treated in some cases before catastrophic clinical sequelae occur. The risk of treatment with alemtuzumab will be thereby mitigated. However current real world (off-trial) clinical systems for ensuring patients actually get monthly blood tests and that the results are checked for early deviations from the norm are not adequate. This study proposes the development of a semi-automated Clinical Decision Support System (CDSS) using international IT pathology standards that checks for the presence of results, analyses the results and determines the need for automated or human alerts as required.

Another risk is that associated with the immunosuppression and the attendant increase in infections and to a lesser extent certain malignancies. Fortunately in the trials this has not been a major problem other than herpes simplex virus which required a trial amendment for prophylaxis. However the trials did not include patients with prior immunosuppressive MS treatment which will occur in the real world. This study proposes the qualitative comparison of a specific patient education module and a standardized risk assessment module extended safety screening system to the procedures used in the CAMMS protocol.

The aim of this study is to develop systems that help mitigate the risk associated with use of alemtuzumab and thereby improve the relationship between benefit and risk from this medication. It is proposed that this study be commenced and the systems developed now as the study anticipates potential regulatory concerns and the systems proposed may help in addressing regulatory concerns and in mitigating post regulatory approval risks of treatment.
Trial website
Trial related presentations / publications
First paper now published, in MSJ, not attached as copyright.
Ref:
Mult Scler. 2018 Jun 1:1352458518783673. doi: 10.1177/1352458518783673.
Successful implementation of an automated electronic support system for patient safety monitoring: The alemtuzumab in multiple sclerosis safety systems (AMS3) study.
Reddel SW1, Barnett MH2, Riminton S3, Dugal T4, Buzzard K5, Wang CT6, Fitzgerald F7, Beadnall HN8, Erickson D9, Gahan D7, Wang D10, Ackland T11, Thompson R12.
Posters attached.
Public notes
Attachments [1] 3020 3020 0 0
Attachments [2] 3021 3021 0 0

Contacts
Principal investigator
Name 42870 0
A/Prof Stephen Reddel
Address 42870 0
Level 5W
1 Hospital Rd
Concord Hospital
NSW 2139`
Country 42870 0
Australia
Phone 42870 0
+612 97676129
Fax 42870 0
Email 42870 0
swreddel@sydneyneurology.com.au
Contact person for public queries
Name 42871 0
Ms Rene Yon
Address 42871 0
Medical Safety Systems
4/94 Mallett St
Camperdown NSW 2050
Country 42871 0
Australia
Phone 42871 0
+612-93510730
Fax 42871 0
Email 42871 0
rene@sydneyneurology.com.au
Contact person for scientific queries
Name 42872 0
A/Prof Stephen Reddel
Address 42872 0
Level 5W
1 Hospital Rd
Concord Hospital
NSW 2139`
Country 42872 0
Australia
Phone 42872 0
+612 97676129
Fax 42872 0
Email 42872 0
swreddel@sydneyneurology.com.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary