Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000185662
Ethics application status
Approved
Date submitted
12/02/2014
Date registered
19/02/2014
Date last updated
14/12/2018
Date data sharing statement initially provided
14/12/2018
Date results information initially provided
14/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Narrow band ultraviolet-B (UVB) light for patients with Clinically Isolated Syndrome
Scientific title
In patients with Clinically Isolated Syndrome, can narrow band UVB therapy decrease the risk of developing Multiple Sclerosis over the 12 months from their first demyelinating event?
Secondary ID [1] 284085 0
Nil known
Universal Trial Number (UTN)
U1111-1153-2803
Trial acronym
PhoCIS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Clinically Isolated Syndrome 291156 0
Multiple Sclerosis 291177 0
Condition category
Condition code
Neurological 291491 291491 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be given narrow band (311 nm) UVB light to their full body on 3 occasions per week. Patients will receive a total of 24 administrations over 8 weeks. They will receive the narrow band UVB light as they stand up in a small cubicle. The exposure to the light will range from 1 to 4 minutes each time.
Intervention code [1] 288780 0
Treatment: Devices
Comparator / control treatment
No administration of narrow band UVB therapy
Control group
Active

Outcomes
Primary outcome [1] 291466 0
Phototherapy-associated changes in the mRNA transcripts and properties of cells in freshly isolated peripheral blood.

The types of cells in freshly isolated blood, the mRNA levels in these cells, and the immunological function of blood cells will be assessed by standard laboratory protocols
Timepoint [1] 291466 0
6 month measurement compared to baseline
Primary outcome [2] 291467 0
Development of a new demyelinating event defined as either (a) a confirmed clinical relapse, or (b) a new cerebral T2 lesion and/or newly Gadolinium-enhancing cerebral lesion as measured in a cerebral MRI.
Timepoint [2] 291467 0
12 month measurement compared to baseline MRI scan
Secondary outcome [1] 306839 0
Phototherapy-associated changes in quality of life measures for the participants with Clinically Isolated Syndrome.

This will be measured by Questionnaires (SF36v2, specially designed lifestyle questionnaires, Fatigue Severity Table)
Timepoint [1] 306839 0
12 month measurement compared to baseline measurement
Secondary outcome [2] 306840 0
Cerebral MRI volume changes.
Timepoint [2] 306840 0
12 month measurement compared to baseline measurement

Eligibility
Key inclusion criteria
Recently diagnosed (within 120 days) with a first isolated, well-defined, uni- or multi-focal first demyelinating event (FDE).
Able to receive their first phototherapy within 120 days of FDE symptom onset.
An MRI brain scan that is supportive of demyelinating disease (Paty A or Paty B criteria, i.e. the presence of at least four T2 lesions greater than 3 mm, or at least three T2 lesions greater than 3 mm, one of which must be periventricular, respectively).
An EDSS between 0 - 6.5 (inclusive)
Must be able to give informed consent and sign the informed consent form
Must be able to comply with all study procedures, and attend 24 phototherapy sessions and centres for venepuncture on multiple occasions during and after phototherapy
If female of child-bearing age, must be willing to use effective contraception
Must be willing to avoid use of sunbeds
Must be able to stand in the phototherapy cubicle for up to 5 minutes at a time
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Known co-morbid illnesses that might be exacerbated by phototherapy, including lupus erythematosus and xeroderma pigmentosum
A history of melanoma, multiple non melanoma skin cancers
Previous prolonged courses of UVB or photochemotherapy (PUVA), or use of sunbeds
Cardiovascular or respiratory disease that would prevent standing in the treatment cubicle
Bullous disease
Use of photosensitizing medications
Very fair skin that burns with very minimal sun exposure (as judged by the dermatologist involved)
Corticosteroids within 3 months, or current immunosuppressive drug therapy (beta-interferon, glatiramer acetate, natalizumab, mitoxantrone, or other chemotherapy agent specifically for demyelinating disease) prior to CIS diagnosis. (*Note that requirement for immunomodulatory therapy in the course of MS disease management will not exclude patients during follow-up; treatment variables will be collected and analysed in both the intervention and control arms in the planned analysis).
Current pregnancy, breastfeeding or planning to become pregnant in the next 12 months.
A second clinical demyelinating event prior to randomisation
Concurrent diagnosis of other neurological, psychiatric or other disease, which, in the opinion of the investigator, could impair capacity to provide informed consent or interfere with study compliance.
Current enrolment in another interventional trial
Any contraindication to MRI scanning or intravenous Gadolinium including: Cardiac Pacemaker, Cardiac Defibrillator, Metal fragments in the eye, Any other non-MRI compatible medical device/implant or medical condition, Previous allergic reaction to Gadolinium, Severe claustrophobia

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be invited to join the trial by neurologists who are treating their first demyelinating event. Once participants have given written informed consent, they will be randomised to receive, or not receive, UVB phototherapy.

Allocation concealment will be performed by a central computer randomisation. It will be obvious to the participants into which group they have been allocated.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised according to computer generated random number table made in Xcel for 60 participants
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Participants who have undergone 2 weeks (6 sessions) of narrow band UVB phototherapy will qualify for intention-to-treat analysis.

Differences in continuous responses between groups will be tested for significance using one-way ANOVA/t-tests or Kruskal-Wallis/Mann-Whitney tests as appropriate to the characteristics of the data. Covariate adjustment will be accommodated via general linear models. Comparisons of binary or categorical variables will be based on Fisher exact or Chi-squared tests, or logistical regression models to incorporate covariate adjustment. Repeated measurements over time will be analysed by longitudinal mixed models.

If new MRI lesions are expected in 90% of CIS patients over 1.5-2 years (CHAMPS, ETOMS, BENEFIT, PRECISE studies), then a treatment effect (ie reduction of 10%) should be discernible with a sample size of 30 patients. Further, in forerunner experiments, in measures of changes in the transcriptome (for 10 transcription factors analysed, blood cells from 11 to 27 patients were required to measure season-related changes to 80% power).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/07/2014
Actual
5/09/2014
Date of last participant enrolment
Anticipated
31/12/2016
Actual
10/03/2017
Date of last data collection
Anticipated
Actual
11/03/2018
Sample size
Target
60
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 2095 0
St John of God Hospital, Subiaco - Subiaco
Recruitment postcode(s) [1] 7772 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 288715 0
Government body
Name [1] 288715 0
National Health and Medical Research Council (NHMRC),
Address [1] 288715 0
Level 1, 16 Marcus Clarke St,
Canberra ACT 2601

Australia
Country [1] 288715 0
Australia
Funding source category [2] 301449 0
Charities/Societies/Foundations
Name [2] 301449 0
Multiple Sclerosis WA
Address [2] 301449 0
Locked Bag 2.
Bentley DC,
WA 6983
Country [2] 301449 0
Australia
Primary sponsor type
University
Name
University of Western Australia
Address
35 Stirling Hwy, Crawley WA 6009
Country
Australia
Secondary sponsor category [1] 287417 0
None
Name [1] 287417 0
Address [1] 287417 0
Country [1] 287417 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290551 0
Belberrry Human Research Ethics Committee
Ethics committee address [1] 290551 0
129 Glen Osmond Road, Eastwood, SA 5063
Ethics committee country [1] 290551 0
Australia
Date submitted for ethics approval [1] 290551 0
19/02/2014
Approval date [1] 290551 0
24/03/2014
Ethics approval number [1] 290551 0
2014-02-083

Summary
Brief summary
People who have experienced for the first time an episode of inflammation within the brain, spinal cord or optic nerves (called a first demyelinating event) are at risk of developing Multiple Sclerosis. In this study, we will test whether a course of narrow band UVB phototherapy decreases their risk of developing Multiple Sclerosis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46222 0
Prof Prue Hart
Address 46222 0
Telethon Kids Institute, PO Box 855, West Perth WA 6872
Country 46222 0
Australia
Phone 46222 0
+61 8 63191566
Fax 46222 0
61 8 63191566
Email 46222 0
Prue.Hart@telethonkids.org.au
Contact person for public queries
Name 46223 0
Prof Prue Hart
Address 46223 0
Telethon Kids Institute, PO Box 855, West Perth WA 6872
Country 46223 0
Australia
Phone 46223 0
+61 8 63191566
Fax 46223 0
+61 8 63191566
Email 46223 0
Prue.Hart@telethonkids.org.au
Contact person for scientific queries
Name 46224 0
Prof Prue Hart
Address 46224 0
Telethon Kids Institute, PO Box 855, West Perth WA 6872
Country 46224 0
Australia
Phone 46224 0
+61 8 63191566
Fax 46224 0
+61 8 63191566
Email 46224 0
Prue.Hart@telethonkids.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Ethics stated confidentiality of data.
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 744 0
Study protocol
Citation [1] 744 0
Link [1] 744 0
Email [1] 744 0
Other [1] 744 0
Attachment [1] 744 0
/Steps11and12/365791-(Uploaded-12-12-2018-18-14-50)-Study-related document.pdf
Type [2] 746 0
Informed consent form
Citation [2] 746 0
Link [2] 746 0
Email [2] 746 0
Other [2] 746 0
Attachment [2] 746 0
/Steps11and12/365791-(Uploaded-12-12-2018-18-16-23)-Study-related document.pdf
Type [3] 748 0
Ethical approval
Citation [3] 748 0
Link [3] 748 0
Email [3] 748 0
Other [3] 748 0
Attachment [3] 748 0
/Steps11and12/365791-(Uploaded-12-12-2018-18-19-24)-Study-related document.pdf
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 749 0
Hart PH, Lucas RM, Booth DR, Carroll WM, Nolan D, Cole JM, Jones AP, Kermode AG. 2017. Narrowband UVB phototherapy for Clinically Isolated Syndrome: A trial to deliver the benefits of vitamin D and other UVB-induced molecules. Frontiers Immunol 8:3. doi: 10.3389/fimmu.2017.00003.
Attachments [1] 749 0
/Steps11and12/365791-(Uploaded-13-12-2018-14-14-40)-Journal results publication.pdf
Publication date and citation/details [2] 768 0
Trend S, Jones AP, Geldenhuys S, Byrne SN, Fabis-Pedrini MJ, Nolan D, Booth DR, Carroll WM, Lucas RM, Kermode AG, Hart PH. 2017. Evolving identification of blood cells associated with Clinically Isolated Syndrome: importance of time since clinical presentation and diagnostic MRI. Int J Mol Sci (section Molecular Pathology, Diagnostics, and Therapeutics, Advances in Multiple Sclerosis 2017) 18(6). pii: E1277. doi: 10.3390/ijms18061277.
Attachments [2] 768 0
/Steps11and12/365791-(Uploaded-13-12-2018-14-10-07)-Journal results publication.pdf
Publication date and citation/details [3] 769 0
Hart PH, Jones AP, Trend S, Cha L, Fabis-Pedrini MJ, Cooper MN, d’Este C, Geldenhuys S, Carroll WM, Byrne SN, Booth DR, Cole JM, Lucas RM, Kermode AG. 2018. A randomised controlled clinical trial of narrowband UVB phototherapy for Clinically Isolated Syndrome: the PhoCIS study. MS Journal: Experimental, Translational, Clinical. 4(2):2055217318773112.
Attachments [3] 769 0
/Steps11and12/365791-(Uploaded-13-12-2018-14-14-40)-Journal results publication.pdf
Publication date and citation/details [4] 770 0
Trend S, Jones AP, Cha L, Byrne SN, Geldenhuys S, Fabis-Pedrini MJ, Carroll WM, Cole JM, Booth DR, Lucas RM, Kermode AG, French MA, Hart PH. Higher serum IgG3 levels may predict the development of multiple sclerosis in individuals with clinically isolated syndrome. Front Immunol 9:1590.
Attachments [4] 770 0
/Steps11and12/365791-(Uploaded-13-12-2018-14-15-47)-Journal results publication.pdf
Publication date and citation/details [5] 771 0
Cha L, Jones AP, Trend S, Byrne SN, Fabis-Pedrini MJ, Carroll WM, Lucas RM, Cole JM, Booth DR, Kermode AG, Hart PH. Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis. Clin Transl Immunol. 7(8): e1037.
Attachments [5] 771 0
/Steps11and12/365791-(Uploaded-13-12-2018-14-16-38)-Journal results publication.pdf
Publication date and citation/details [6] 772 0
Ghaly S, Bliuc D, Centre J, Clarke MW, Jones AP, Trend S, Kermode AG, Neale RE, Hart PH. Vitamin D C3-epimer levels are proportionally higher with oral vitamin D supplementation compared to ultraviolet irradiation of skin in mice but not humans. J Ster Biochem Mol Biol, Oct 5. Doi: 10.1016/j.jsbmb.2018.10.002
Attachments [6] 772 0
/Steps11and12/365791-(Uploaded-13-12-2018-14-18-55)-Journal results publication.pdf
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary
As preclinical studies have suggested that exposure to ultraviolet radiation could reduce the development of MS, the Phototherapy for CIS (PhoCIS) trial was established to examine the effect of narrowband UVB phototherapy on patients with Clinically Isolated Syndrome (CIS), and their conversion to MS. By 12 months, 100% of those in the no phototherapy arm and 70% in the phototherapy arm had converted to MS. This difference was not statistically significant but provides the basis for further studies of narrowband UVB irradiation on MS progression.