Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05281640 |
| Other study ID # |
123 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 28, 2022 |
| Est. completion date |
August 31, 2023 |
Study information
| Verified date |
February 2024 |
| Source |
Edinburgh Napier University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Psychosis is a highly distressing mental health condition, affecting up to 3% of the
population. Conceptually, it has much in common with complex post-traumatic stress disorder
(CPTSD), a recently introduced condition in ICD-11. Both involve negative self-esteem,
impaired emotion regulation ability, interpersonal difficulties and intrusive trauma- related
experiences (i.e. intrusive thoughts, flashbacks, nightmares). Both have been causally
related to childhood trauma, such as abuse, neglect and loss.
The current project will examine the feasibility of conducting an 'Umbrella trial' to test
whether CPTSD is causally related to psychosis, and develop more effective trauma-focused
psychological interventions for psychotic symptoms by treating underlying experiences
of/reactions to trauma. An Umbrella trial involves running several individual randomised
controlled trials concurrently. In this study, each trial will test whether psychological
interventions designed to reduce different CPTSD symptoms cause improvements in psychotic
symptoms. If the investigators can establish feasibility of this Umbrella trial, and if a
definitive version shows that interventions for CPTSD also reduce psychosis, then this would
be a breakthrough in both the conceptualisation and treatment of psychosis which will help
transform the care of people with psychosis. Demonstrating the feasibility of our proposed
methodology would also help to accelerate the development of interventions for other mental
health problems.
Description:
BACKGROUND & RATIONALE FOR STUDY
Psychosis, characterised by unusual experiences such as delusions and hallucinations, is
commonly associated with a diagnosis of schizophrenia. It affects up to 3% of the population,
and individuals with this condition often experience high levels of distress, a loss of
ability to plan and work, and a loss of interpersonal relationships. People with psychosis
die 15-20 years earlier than the general population, however existing treatments for
psychosis have at best modest effects on symptoms and related distress. Consequently, many
thousands of people are left with highly distressing symptoms that remain resistant to
current treatment.
Exposure to childhood trauma substantially increases the risk of developing psychosis.
Post-traumatic stress disorder (PTSD) and psychosis frequently co-occur and PTSD is a known
risk factor for later psychosis. However, strategies to treat PTSD in psychosis have had
limited success. This may be because psychosis overlaps with a more complex condition than
PTSD, namely Complex PTSD (CPTSD). CPTSD, now recognised in the 11th revision of the World
Health Organisation's International Classification of Diseases (ICD-11), is defined as PTSD
(i.e. intrusive thoughts, avoidance of reminders of the traumatic memory and hyperarousal)
and co-occurring symptoms of affect dysregulation (AD), negative self-concept (NSC), and
disturbed relationships (DR). These symptom domains, which are commonly referred to as
Disturbances of Self-Organisation (DSO), are also highly prevalent in psychosis, and they
appear to mediate the relationship between childhood adversity and psychotic symptoms. In a
recent pilot study (n=85), 41% of people with psychosis endorsed symptoms of CPTSD,
confirming that CPTSD and psychosis very frequently co-occur. Thus, psychological treatments
that reduce CPTSD symptoms might represent a new direction in both the conceptualisation and
treatment of psychosis.
Although there is strong observational evidence that traumatic stress may cause psychosis via
CPTSD symptoms, this relationship has not been tested experimentally. Furthermore, although
there are existing psychological interventions for CPTSD symptoms, it is unknown whether they
are effective at reducing psychotic symptoms. Based on an established effective therapy for
complex traumatisation (Skills Training in Affective and Interpersonal Regulation; STAIR),
the investigators have recently devised a treatment protocol for CPTSD (Enhanced STAIR for
CPTSD - ESTAIR with three 6-session modules targeting individual DSO symptom clusters of
CPTSD (AR, NSC & DR). The next stage of our research will focus on whether targeting DSO
symptoms in people with psychosis can improve treatments for psychosis. The investigators
will examine the feasibility of conducting an 'Umbrella trial' to test whether CPTSD symptoms
are causally related to psychosis, and develop more effective trauma-focused psychological
interventions for psychosis. This involves running three single-blind
'interventionist-causal' randomised controlled trials (IC-RCTs) concurrently, each testing
whether an individual ESTAIR DSO module (addressing either AD, NSC or DR) causes improvements
in psychotic symptoms. Recommended to accelerate the treatment of psychotic symptoms such as
delusions, running these sophisticated trials concurrently can produce significant findings
10-15 years earlier compared to running each trial individually. If the feasibility of this
Umbrella trial can be established, defined as successful recruitment and retention of
participants with psychosis, the investigators will seek funding to conduct a definitive
trial.
AIMS and RESEARCH QUESTIONS
Aim 1: Adapt an existing CPTSD modular intervention (ESTAIR) so that it can be used with
people with psychosis (RQ 1)
Aim 2: Test feasibility, acceptability, and safety of the CPSTD modular therapy in people
with psychosis (RQ 2,3)
Aim 3: Test recruitment rates, data quality and trial procedures for a definitive Umbrella
(RQ 3,4)
Research questions (RQ):
RQ 1: Can an effective CPTSD intervention (ESTAIR) be adapted and used to help individuals
with psychosis?
RQ 2: What proportion of eligible individuals participate, engage, and complete the
interventions as part of the Umbrella trial?
RQ 3: What proportion of eligible individuals participate in, engage with and complete
research assessments, and what data quality and completion rates can therefore be obtained?
RQ 4: What sample size is required for a definitive trial?
STUDY DESIGN
Following consultation with NIHR EME, this study has been designed to ensure the
investigators can successfully recruit and retain participants in a larger trial
characterised by the same design parameters (e.g., allocation ratio, blind assessment, types
of treatment and control offered, multiple sites). The proposed randomised pilot study is
therefore a 20-month feasibility/pilot of a multi-site single (rater) blind Umbrella trial of
psychological interventions to treat CPTSD symptoms in people diagnosed with non-affective
psychosis (schizophrenia-spectrum disorders). It has been designed primarily to examine
post-treatment (8 week) data retention rates for the planned primary outcome (PANSS;
psychotic symptoms) in a future definitive trial. In this and the future study, participants
will be randomly allocated to receive treatment as usual (TAU) plus a psychological
intervention to improve (i) affect dysregulation (AD), (ii) negative self-concept (NSC), or
(iii) disturbed relationships (DR), or TAU alone by way of control condition.
To ensure recruitment from a large pool of participants from multiple sites, 50% of the
sample will be recruited from the lead site (NHS Lothian) and 50% from NHS Greater Glasgow
and Clyde. Each intervention group will be compared to its own control group (each will
receive the same standardised procedure) to ensure participants in each trial are equivalent
with respect to their presenting mechanism.
Participants & setting: Adults (aged 18-65) diagnosed with schizophrenia-spectrum disorder,
and presence of AD, NSC or DR (as a result of exposure to traumatic life events) will be
recruited from inpatient and outpatient NHS mental health services across two Scottish sites;
50% from NHS Lothian; 50% from NHS Greater Glasgow and Clyde.
Allocation and randomisation: Participants will be randomly assigned to one of the two-arm
IC-RCTs based on whether they present with AD, NSC or DR (score ≥2 in each domain as assessed
by the ITQ). Participants with multiple mechanisms will be randomly assigned. All
participants will be randomised (1:1) to either treatment or control using Sealed Envelope
online randomisation prior to the start of treatment session 1.
Interventions and control: Each of the three ESTAIR DSO modules is structurally equivalent (6
sessions each over 8 weeks) and will be delivered by the same trained therapist. Each has
been designed to reduce symptoms of a specific CPTSD symptom cluster (AD, NSC or DR).
Participants allocated to intervention will receive one of the three 6-session modules, over
an 8-week window.In the full trial it will be monitored whether TAU moderates outcomes by
using an appropriate tool (i.e. Client Receipt Service Inventory; CSRI).
Data collection & masking: Clinical research data will be gathered at baseline,
post-intervention (week 8) and follow-up (week 12). RAs will be masked to group allocation to
demonstrate to future funders this is achievable in an Umbrella trial. Blind-breaks will be
recorded, and minimised using previously successful strategies (e.g., separate offices /
diaries).
Data Analysis: Blind analysis of outcome data according to a fully pre-registered plan will
be conducted. Proportions, means, SDs, effect sizes and 95% CIs for all time points will be
reported descriptively on both a strict intention-to-treat and per-protocol basis (≥50%
attendance in treatment or control). Missing data due to attrition will be minimised by
maintaining up to two phone contacts with participants between assessments.
Progression criteria for a full trial: the investigators will progress if the recruitment
target is achieved and post-intervention (8 week) PANSS data is acquired from ≥75% of those
randomised (45).
Research Team & Expert Advisory Group
This project will receive strong support from: A) An Expert Advisory group: This will include
an expert by experience with interest in research in trauma and psychosis B) An experienced
multi-disciplinary research team: the team has been chosen to ensure it comprises clinical,
academic and methodological experience and expertise in all relevant areas required for
successful completion of the project.
STUDY POPULATION
NUMBER OF PARTICIPANTS NIHR guidance was used to calculate that 60 participants (2 per month
per site over 15-months) will allow us to estimate a drop-out rate (i.e. data non-retention)
of 15%, at week 8, to within a 95% confidence interval of +/- 10%. The proportion of people
with schizophrenia-spectrum disorders who have at least one of our proposed causal mechanisms
is estimated to be approximately 40%.
IDENTIFYING AND RECRUITMENT OF PARTICIPANTS As per previous trials in the field of psychosis,
local site leads will enable RAs to visit clinical services to present the trial, determine
initial interest, and distribute information sheets. Referrers will seek consent from
potential participants to be contacted by the researchers. Those consenting will be given a
participant information sheet and any initial questions will be answered. They will be
re-contacted after a minimum period. Those consenting will be assessed. Those eligible will
enter the trial.
Self referral will be accepted. A poster will be placed in NHS mental health services to
advertise the study. If an individual self-refers, they will only be included if they agree
to the investigators contacting a mental health professional involved in their care, to
obtain information for risk assessment purposes and to ensure participation is not
contraindicated in some way.
CONSENTING PARTICIPANTS Only include adults who have capacity to consent to research will be
included. For potential participants entering the study through the clinician-referral
recruitment pathway, their clinician will discuss the study with them, answer any questions,
give them an information sheet and seek their verbal consent to pass on their details to the
research team, and allow them to complete an initial risk assessment. A trained and
supervised research assistant (RA) will then contact clinicians to gather contact details for
potential participants and complete the risk assessment. The RA will then contact potential
participants directly to discuss the study further and answer any questions.
For potential participants entering the study through self-referral, the RA will obtain their
explicit verbal consent to contact their keyworker/ care-coordinator to determine whether
they meet inclusion criteria for the study and to complete an initial risk assessment. The RA
will also ask the clinical care team if they have any concerns about the potential
participant's capacity to consent to take part in research. Should participants meet
inclusion criteria for the study and continue to express an interest in taking part, the RA
will contact them to arrange an appointment. All potential participants will have as long as
they wish to consider the information sheet prior to being contacted by the RA, with a
minimum period of 48 hours. The information sheet will detail what participants are asked to
do, how their information will be used and the possible risks and benefits of taking part in
the study.
PARTICIPANT WITHDRAWAL Participants are free to withdraw from the study at any point, without
giving any reason and without their legal rights or usual care being affected. Investigators
may also withdraw participants if they deem their continuation to be harmful.
Advance consent will be sought from all participants to retain their existing data should
they subsequently withdraw due to loss of contact or loss of capacity to consent to research,
where they have not otherwise informed us they wish their data to be removed.
See information below regarding Serious Adverse Events.
STUDY SUSPENSION OR DISCONTINUATION The research would be stopped in the event of a number of
SAEs which are deemed attributable to participation in PICASSO. All SAEs will be passed on to
the independent Data Monitoring and Ethics Committee (DMEC) for review, who would have
responsibility for advising the Chief Investigator and Sponsor as to whether they are
attributable to study participation, setting the threshold for discontinuation and issuing
advice to suspend or discontinue. After taking into account advice from the DMEC and
consulting with the Chief Investigator, the Sponsor and Research Ethics Committee (REC) will
make the final determination on whether the trial will continue or not. See Section 9 for
more details.
ADVERSE EVENTS
PARTICIPANTS The interventions have been used previously with people with CPTSD, including in
randomised controlled trials and no severe adverse events have been reported. However, the
investigators wish to improve the recording and reporting of adverse effects of psychological
interventions, and have therefore developed a robust protocol for assessing and managing any
such risk, which will be completed at end of treatment and at follow-up by RAs masked to
treatment condition. Using an approach adapted from the DEC:IDES trial serious adverse events
will be defined as (i) death by suicide; (ii) suicide attempt; (iii) suicidal crisis without
attempt ; (iv) severe symptom exacerbation (rating of ≥6 on the patient or researcher-rated
Clinical Global Impression Scale (CGI) and CGI-Improvement scale). Non-severe adverse events
will be defined as a score of ≥3 (agree 'quite a lot' or 'a lot') on any relevant item (e.g.,
subjectively worsening mental state, heightened stigma, increased medication use, increased
conflict) on the patient-rated 27-item Adverse Events Questionnaire.
This protocol, excluding the Adverse Events Questionnaire (which is designed to be completed
after treatment), will also be completed by clinicians during the intervention (i.e., every
session) to complete an assessment of severe adverse events. This will be primarily for
clinical purposes, although scores will also be reported to the DMEC, the Sponsor, and in the
final paper.
As noted above, the DMEC will review each serious adverse event (SAEs) and provide an
independent assessment to the Sponsor (Edinburgh Napier University) of whether or not it is
likely to be attributable to the person's participation in PICASSO. The Sponsor will make the
final decision as to whether the SAE was attributable to participation, and therefore whether
it needs to be reported to the NHS REC.
The research would be stopped in the event of a number of SAEs which are deemed attributable
to participation in PICASSO. All SAEs will be passed on to the independent DMEC for review,
who would have responsibility for advising the Chief Investigator and Sponsor as to whether
they are attributable to study participation, setting the threshold for discontinuation and
issuing advice to suspend or discontinue. After taking into account advice from the DMEC and
consulting with the Chief Investigator, the Sponsor and REC will make the final determination
on whether the trial will continue or not. See Section 9 for more details.
