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Trial registered on ANZCTR


Registration number
ACTRN12618001939280
Ethics application status
Approved
Date submitted
20/11/2018
Date registered
29/11/2018
Date last updated
29/11/2018
Date data sharing statement initially provided
29/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Sofosbuvir/Velpatasvir and Mental Health Impact in people with Lived Experience and Hepatitis C infection - SMILE-C Trial
Scientific title
Sofosbuvir/Velpatasvir and Mental Health Impact in people with Lived Experience and Hepatitis C infection - SMILE-C Trial
Secondary ID [1] 296654 0
IN-AU-342-4672
Universal Trial Number (UTN)
U1111-1224-2578
Trial acronym
SMILE-C Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatitis C virus infection 310486 0
Schizophrenia 310487 0
Schizoaffective disorder 310488 0
Bipolar disorder 310489 0
Cognitive dysfunction 310490 0
Condition category
Condition code
Infection 309196 309196 0 0
Other infectious diseases
Mental Health 309197 309197 0 0
Schizophrenia
Mental Health 309198 309198 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial is a double blind placebo randomised control trial (RCT) using an immediate versus deferred direct-acting antiviral (DAA) treatment strategy (24 week delay). Participants are randomised to one of the two treatment groups:

Group 1 (immediate treatment): Immediate treatment with Sofosbuvir/Velpatasvir daily for 12 weeks, with follow-up 12 weeks thereafter (SVR12 check: week 24).

Group 2 (deferred treatment): Matched placebo daily for 12 weeks and follow-up 12 weeks thereafter (SVR12 check: week 48) with Sofosbuvir/Velpatasvir treatment.

At week 24, following a second round of neuropsychological testing the trial will be unblinded and the participants in Group 2 will be informed that they had received the matched placebo. These Group 2 participants will then commence open-label Sofosbuvir/Velpatasvir for 12 weeks, with follow-up 12 weeks thereafter (SVR12; week 48).

Our model of care follows recommendations such as prescribing Sofosbuvir/Velpatasvir on a monthly basis and contacting the participant at least once between visits. Participants will receive follow-up phone calls at weeks two, six, 10 and 12 to monitor adherence. Prior to receiving the the next month supply of the trial drug the participant will be asked to return the container and any remaining tablets from the previous month.
Intervention code [1] 312962 0
Treatment: Drugs
Comparator / control treatment
The Placebo consists of microcrystalline Cellulose, Colloidal Silicon Dioxide, Sodium Starch Glycolate and Sodium Stearyl Fumarate.
Control group
Placebo

Outcomes
Primary outcome [1] 308171 0
Comparison of total Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score between the randomised groups at week 24.
Timepoint [1] 308171 0
The Primary endpoint will be measured at week 24.
Secondary outcome [1] 354144 0
Proportion of participants achieving cure of chronic hepatitis C infection ("sustained virological response (SVR)") as assessed at 12 weeks post completion of treatment. Assessment will be performed on the participant's blood by Nucleic acid testing for the presence of detectable Hepatitis C Virus.
Timepoint [1] 354144 0
The secondary endpoints will be measured at 24 and 48 weeks.
Secondary outcome [2] 354145 0
Proportion of participants completing a 12 week course of sofosbuvir/velpatasvir. As assessed by the proportion of participants returning empty trial drug bottles at schedule visits. The trial drug will be administered over three, one monthly intervals (28 tablets/month). The participant will be asked to return any remaining tablets prior to receiving the next month supply of the trial drug.
Timepoint [2] 354145 0
The secondary endpoints will be measured at 24 and 48 weeks.
Secondary outcome [3] 354146 0
Adherence to Sofosbuvir/Velpatasvir DAA treatment. The participant will be asked to return any remaining tablets prior to receiving the next month supply of the trial drug.
Timepoint [3] 354146 0
The secondary endpoints will be measured at 24 and 48 weeks.
Secondary outcome [4] 354147 0
Additional and specific neuropsychological testing performance: Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and THINC-it tool.
Timepoint [4] 354147 0
The secondary endpoints will be measured at 24 and 48 weeks.
Secondary outcome [5] 354447 0
Measure of psychotic symptoms using the Brief Psychiatric Rating Scale (BPRS).
Timepoint [5] 354447 0
The secondary endpoints will be measured at 24 and 48 weeks.
Secondary outcome [6] 354453 0
Measure of depressive symptoms/anxiety using the Montgomery-Asberg Depression Scale (MADRS).
Timepoint [6] 354453 0
The secondary endpoints will be measured at 24 and 48 weeks.
Secondary outcome [7] 354454 0
Measure of psychosocial functioning using the Functioning Assessment Short Test (FAST) and Global Assessment of Functioning (GAF).
Timepoint [7] 354454 0
The secondary endpoints will be measured at 24 and 48 weeks.
Secondary outcome [8] 354455 0
Measure quality of life using the World Health Organization Quality of Life Instrument (WHOQOL-BREF).
Timepoint [8] 354455 0
The secondary endpoints will be measured at 24 and 48 weeks.

Eligibility
Key inclusion criteria
• 18 years of age or above
• HCV RNA positive detected by PCR (PCR to be repeated if older than 12 months)
• Established and stably treated schizophrenia, schizoaffective disorder or bipolar disorder, i.e. stably treated defined as no expected significant changes to the participant’s mental health treatment within six months after the baseline visit
• HCV treatment naïve or experienced (defined as prior exposure to interferon-based therapy)
• A comprehensive understanding of verbal and written English
• Capacity to provide informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Unstable mental health status at time of enrolment requiring acute intervention (e.g. psychosis, mania, suicidal depression)
• Prior failure of a NS5A inhibitor containing antiviral regimen
• Decompensated liver disease
• Need for addition of ribavirin to the Sofosbuvir/Velpatasvir
• eGFR<30 mL/min1.73m2
• Pregnant and breastfeeding women. Birth control whilst taking Sofosbuvir/Velpatasvir will be discussed
• HIV coinfection
• Taking any drug with known reported significant interactions with Sofosbuvir/Velpatasvir https://www.hep-druginteractions.org/checker

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)
Allocation concealment will be centrally controlled using a password protected on-line computerised randomisation service hosted on REDCap at the University of Adelaide.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified by site using randomly permuted blocks (to minimise any imbalance between treatment and placebo groups) and will be generated by a statistician otherwise not involved in the trial.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
This trial is a double blind placebo randomised control trial (RCT) using an immediate versus deferred direct-acting antiviral (DAA) treatment strategy (24 week delay).

At week 24, following a second round of neuropsychological testing the trial will be unblinded. The participants who received the placebo will then commence open-label Sofosbuvir/Velpatasvir for 12 weeks, with follow-up 12 weeks thereafter (SVR12; week 48).
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We aim to recruit 150 participants with severe and enduring mental illness. The power calculations for this trial are based upon the hypothesis that successful HCV treatment with DAA based therapy is associated with improved neuropsychological performance. Preliminary power calculations were carried out with consideration of expected changes in neurocognitive tests, as per previous reports in the literature; here, medium to large effect sizes of improvement between d= 0.20 to d= 1.79 (depending on the individual test) following DAA treatment have been described.

We based our priori power calculation on an effect size of d=0.5 for treatment-associated changes on the R-BANS total score. We assumed that differences between immediate and deferred treatment groups would be largest at the week-24 assessment time point. To detect d=0.5 with a power of 0.8 and a Type 1 error probability of a=0.05 using a two-tailed t-test, we require a total sample size of 128 participants (64 per trial group).

All analyses will be undertaken according to a comprehensive statistical analysis plan developed and signed off by the trial team before database lock. The primary analysis will be performed on the modified intention to treat population defined as all those participants randomised who attend at least one visit following enrolment.

Recruitment
Recruitment status
Not yet recruiting
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,SA
Recruitment hospital [1] 12450 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [2] 12451 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [3] 12452 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 12453 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [5] 12455 0
Noarlunga Health Service - Noarlunga Centre
Recruitment hospital [6] 12456 0
Prince of Wales Hospital - Randwick
Recruitment hospital [7] 12457 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [8] 12458 0
Westmead Hospital - Westmead
Recruitment hospital [9] 12459 0
St George Hospital - Kogarah
Recruitment hospital [10] 12460 0
Liverpool Hospital - Liverpool
Recruitment hospital [11] 12461 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [12] 12462 0
Glenside Campus - Glenside
Recruitment hospital [13] 12463 0
Mount Gambier and Districts Health Service - Mount Gambier
Recruitment hospital [14] 12464 0
Millicent and District Hospital and Health Services - Millicent
Recruitment postcode(s) [1] 24734 0
5112 - Elizabeth Vale
Recruitment postcode(s) [2] 24735 0
5011 - Woodville
Recruitment postcode(s) [3] 24736 0
5000 - Adelaide
Recruitment postcode(s) [4] 24737 0
5042 - Bedford Park
Recruitment postcode(s) [5] 24739 0
5168 - Noarlunga Centre
Recruitment postcode(s) [6] 24740 0
2031 - Randwick
Recruitment postcode(s) [7] 24741 0
2050 - Camperdown
Recruitment postcode(s) [8] 24742 0
2145 - Westmead
Recruitment postcode(s) [9] 24743 0
2217 - Kogarah
Recruitment postcode(s) [10] 24744 0
2170 - Liverpool
Recruitment postcode(s) [11] 24745 0
2010 - Darlinghurst
Recruitment postcode(s) [12] 24746 0
5065 - Glenside
Recruitment postcode(s) [13] 24747 0
5290 - Mount Gambier
Recruitment postcode(s) [14] 24748 0
5280 - Millicent
Recruitment postcode(s) [15] 24749 0
5108 - Salisbury
Recruitment postcode(s) [16] 24750 0
5113 - Elizabeth Park
Recruitment postcode(s) [17] 24751 0
5112 - Elizabeth East
Recruitment postcode(s) [18] 24752 0
5092 - Modbury
Recruitment postcode(s) [19] 24753 0
5073 - Tranmere
Recruitment postcode(s) [20] 24754 0
5011 - Woodville Park
Recruitment postcode(s) [21] 24755 0
5046 - Oaklands Park
Recruitment postcode(s) [22] 24757 0
5168 - Noarlunga Downs
Recruitment postcode(s) [23] 24758 0
5700 - Port Augusta
Recruitment postcode(s) [24] 24759 0
5291 - Mount Gambier
Recruitment postcode(s) [25] 24760 0
2050 - Missenden Road
Recruitment postcode(s) [26] 24761 0
2170 - Liverpool South
Recruitment postcode(s) [27] 24763 0
2031 - Clovelly
Recruitment postcode(s) [28] 24764 0
2217 - Kogarah Bay
Recruitment postcode(s) [29] 24765 0
2010 - Surry Hills
Recruitment postcode(s) [30] 24766 0
5280 - Beachport

Funding & Sponsors
Funding source category [1] 301234 0
Commercial sector/Industry
Name [1] 301234 0
Gilead Sciences, Inc.
Address [1] 301234 0
417 St Kilda Road
Melbourne Vic 3004

Country [1] 301234 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
Faculty of Health and Medical Sciences,
North Terrace,
Adelaide, South Australia 5005
Country
Australia
Secondary sponsor category [1] 300865 0
None
Name [1] 300865 0
Address [1] 300865 0
Country [1] 300865 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301974 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 301974 0
Ground Floor, Basil Hetzel Institute for Translational Health Research, 28 Woodville Road, Woodville South, South Australia 5011
Ethics committee country [1] 301974 0
Australia
Date submitted for ethics approval [1] 301974 0
07/09/2018
Approval date [1] 301974 0
09/11/2018
Ethics approval number [1] 301974 0
HREC/18/CALHN/617

Summary
Brief summary
Hepatitis C virus (HCV) infection has itself been associated with impaired neuropsychological performance. Up to 50% of people diagnosed with HCV have reported neuropsychiatric disorders and neurocognitive dysfunction. People with schizophrenia, schizoaffective disorder and bipolar disorder suffer disproportionately high rates of HCV-infection. We hypothesis, that successful HCV treatment with DAA-based therapy is associated with improved neurocognitive function in people with severe mental illness. This may be particularly important for patients’ overall functioning and for quality of life in this marginalised and understudied population.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88730 0
Prof Mark Boyd
Address 88730 0
The University of Adelaide, Faculty of Health and Medical Sciences
Level 2, Lyell McEwin Hospital, Haydown Road, Elizabeth Vale, SA 5112
Country 88730 0
Australia
Phone 88730 0
+61 8 81829653
Fax 88730 0
+61 8 81829654
Email 88730 0
mark.boyd@adelaide.edu.au
Contact person for public queries
Name 88731 0
Prof Mark Boyd
Address 88731 0
The University of Adelaide, Faculty of Health and Medical Sciences
Level 2, Lyell McEwin Hospital, Haydown Road, Elizabeth Vale, SA 5112
Country 88731 0
Australia
Phone 88731 0
+61 8 81829653
Fax 88731 0
+61 8 81829654
Email 88731 0
mark.boyd@adelaide.edu.au
Contact person for scientific queries
Name 88732 0
Prof Mark Boyd
Address 88732 0
The University of Adelaide, Faculty of Health and Medical Sciences
Level 2, Lyell McEwin Hospital, Haydown Road, Elizabeth Vale, SA 5112
Country 88732 0
Australia
Phone 88732 0
+61 8 81829653
Fax 88732 0
+61 8 81829654
Email 88732 0
mark.boyd@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This data will be deidentified and reported in aggregate.
What supporting documents are/will be available?
No other documents available
Summary results
No Results