INTernational REsearch Programme on Psychosis In Diverse Settings

Psychotic Disorders Clinical Trial

— INTREPID II  

Official title:

Protocol for a Multi-study Programme of Research on Untreated Psychosis in India, Nigeria, and Trinidad

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04336137
• Other study ID #: HR-17/18-5601
• Secondary ID: MR/PO25927/11580
• Status: Recruiting
• Start date: May 1, 2018
• Est. completion date: June 30, 2022

Study information

• Verified date: March 2020
• Source: King's College London
• Contact: Professor Craig Morgan
• Phone: (+44)20 7848 0351
• Email: craig.morgan[@]kcl.ac.uk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

INTREPID II aims to investigate variability in incidence, presentation, outcome, and impact of untreated psychotic disorders in three countries - India, Nigeria, and Trinidad - through four interconnected observational studies:

1. Study 1 on Incidence, Presentation, and Risk has the objective to investigate the incidence and presentation of untreated psychotic disorders in each setting and associated risk factors.

2. Study 2 on Course and Outcome has the objective to investigate two-year course and outcome of psychotic disorders and associated factors.

3. Study 3 on Help-seeking and Impact has the objective to investigate (a) help-seeking; and (b) the impact of psychotic disorders on individuals and families, using a combination of quantitative and qualitative approaches.

4. Study 4 on Physical Health has the objective to investigate the types and prevalence of physical health problems and related biological markers.

Description:

INTREPID II comprises four interconnected studies. As a basis for these studies, the researchers are identifying, assessing, and following, in each catchment area, population-based cohorts of cases (individuals with an untreated psychotic disorder) and controls (individuals with no history of a psychotic disorder). In each setting, the researchers will identify, assess, and follow at 2 years cohorts of 240 cases with a psychotic disorder (total, 720) and 240 matched controls (total, 720), using methods and infrastructure developed during a feasibility and pilot study, INTREPID I. The inclusion and exclusion criteria for cases are in line with those used in previous studies, including the World Health Organization (WHO) multi-country studies, and are purposefully broad to capture heterogeneity and to allow sub-analyses by duration of untreated psychosis.

The study sample includes cases, controls and relatives or caregivers:

Sample (1) Cases

To estimate incidence, the researchers aim to identify all individuals with an untreated psychotic disorder (cases) within each catchment area. Untreated is defined as never having received treatment with anti-psychotic medication for one continuous month prior to the start of the case-finding period.

In each catchment area, the researchers are using a multi-pronged approach to case identification. First, using procedures developed in INTREPID I, the researchers have established comprehensive case detection systems by mapping and seeking to engage a comprehensive set of service providers and community key informants who may encounter individuals with psychotic disorders within the catchment area. This includes the professional sector (specialist and generalist services; public, private and third sector), the folk sector (including traditional and religious services), and the popular sector (i.e. informal sources of support). Second, the researchers give providers and informants materials developed in the INTREPID I pilot work that detail, using local terms and language, the experiences and behaviours that characterise psychosis. Third, in each catchment area, researchers check with each provider and informant regularly and conduct regular checks of admissions ledgers and registers for in-patient and out-patient services (where these exist), to identify potential cases. In addition, in rural villages in Chennai and Ibadan, field workers visit village meeting points to enquire about potential cases. Potential cases are then screened for inclusion using the Screening Schedule for Psychosis, an instrument that has been widely used in epidemiological studies of psychoses. Those who screen positive and who meet inclusion criteria are approached and informed consent sought.

Case-finding began on 1 May 2018 and will conclude 30 April 2020. At the end of the case-finding period, the researchers will conduct leakage studies in each setting to identify possible cases meeting the study's inclusion criteria who may not have been identified. Each research team will systematically re-check admissions ledgers and registers for in-patient and out-patient services and complete final checks with healers and key informants.

All eligible cases identified through the incidence study are invited to participate in the programme. Rates of refusal are documented and basic data (i.e. age, gender, area of residence, sector of identification, and where possible ethnicity, religion, duration of untreated psychosis and mode of onset) is collected for those who decline to participate, or who it is not possible to interview, to assess non-response bias.

Sample (2) Controls

Age-, sex- and neighbourhood-matched controls are recruited to provide indicative population data against which to compare cases in terms of hypothesised risk factors, social outcomes, and physical health. The researchers use the Psychosis Screening Questionnaire to collect information on any current or past experiences of psychosis. In the absence of a readily accessible sampling frame to randomly select potential controls, the researchers map the ten nearest neighbouring households for each case, listing all residents in these dwellings by sex and age. All potential controls for the case (defined as the same gender and ±5 years of age) are then approached in random order, until an eligible control is identified. When no match is identified the process is repeated. This approach was successfully piloted in all settings.

Sample (3) Relatives and Caregivers

The researchers seek consent from each case to approach a close relative or caregiver to participate in the study. They then approach each designated relative to seek his/her consent. The primary purposes of including relatives are to corroborate and extend information from cases (e.g., physical health and illness), to collect information on premorbid adjustment, family history of mental disorder, and other risk factors, and to collect information on family responses to psychosis, help-seeking, and impact (burden) on family.

Follow-up

All participants will be followed at 2 years. To facilitate this, the researchers collect detailed contact information at baseline (address, telephone number, email address if applicable, service provider details) from each case and control, including details of a relative or friend who can be contacted to trace the individual. In addition, to maintain contact and minimise attrition, the researchers contact participants every six months, by telephone or in person, to confirm or update contact details. Based on the INTREPID I pilot work, the researchers expect to re-assess around 80% of cases and controls 2 years after initial identification.

Sample size

In each setting, the researchers anticipate (based on pilot findings) identifying around 300 untreated cases. Of those, given an expected refusal rate of 20% of all eligible cases (based on the INTREPID I pilot work), the researchers anticipate recruiting approximately 240 cases with a psychotic disorder (total, 720), and 240 individually matched controls (total, 720). These sample sizes are larger than most previous studies and provide good statistical power to test the study hypotheses (i.e., > 80% at p 0.05). For example: (1) with samples of around 300 incident cases in each setting, the researchers will have over 80% power to detect an incidence rate ratio of 1.5 (or greater) between two areas (e.g., urban vs. rural), if the incidence rate in the lowest risk area is 20 per 100,000; (2) with a sample of 240 cases and 240 controls in each setting, the researchers will have over 80% power to detect an odds ratio of 2.0 (or greater) in case-control comparisons when the prevalence of exposure (risk factor) is at least 15% in controls; (3) using gender as an example, with a sample of 192 cases followed at 2 years in each setting, the researchers will have 80% power (or greater) to detect a difference in the proportion of cases with a poor outcome (e.g., continuously psychotic) of 0.20 (20%) or greater, when the proportion of men with a poor outcome is 0.40 and the proportion of women is 0.20 (i.e., equivalent to an odds ratio of ~ 2.5).

Data collection

To test the hypotheses and address the research questions of INTREPID II's four studies, the researchers collect information from cases, relatives, and controls at baseline and at 2 year follow up. All measures, where necessary, have been translated into local languages and back translated to check equivalence.

All those who consent are interviewed and assessed by trained research workers using structured instruments and protocols either at home or at a local clinic. For participants who are in contact with health services, interview data are supplemented with reference to clinical notes, with participants' consent.

Interviews and assessments are conducted by researchers fluent in the local language. To ensure consistency of methods across settings, all researchers are fully trained using a mixture of online materials and exercises, with feedback, and face to face training, delivered both by the United Kingdom (UK) team and locally by senior researchers under the supervision of the country principal investigators (PIs). All PIs are experienced psychiatrists with extensive backgrounds in both national and international research. Inter-rater reliability for core instruments that require rater judgement will be tested regularly across settings using video-recorded interviews with cases and controls to ensure that the measures are applied consistently throughout the duration of the programme. Responses will be triangulated with relative reports and, where applicable, clinical records.

Reliability

All measures will be applied identically, by the same research team, for both cases and controls (where measures apply to both groups). Researchers from across the field settings rated video-taped interviews at study onset and their ratings were compared to gold standard responses developed by the PIs.

Analysis Plan

The researchers will use standard summary statistics, with indicators of spread and precision as appropriate (e.g., crude incidence rates per 100,000 person years, with 95% confidence intervals) to describe the data. They will then use appropriate regression models to compare data between and within settings (e.g., Poisson regression for incidence rates and other count data; Cox regression for time-to-event data; logistic regression (including multinomial) for categorical data [e.g., course type]; and linear regression for continuous data [e.g., GAF score, blood pressure]). In building regression models, the researchers will first fit univariable models, then test for effect modification by core variables (e.g., gender, age, setting, and time), and finally adjust for putative confounders of each hypothesised association by fitting multivariable models.

Where appropriate, the researchers will use multiple imputation to deal with missing data. In addition, or where assumptions necessary for imputation are not met, researchers will (re) conduct analyses on participants with complete data only. Where possible, analyses based on imputed data will be presented, with complete data analyses presented as sensitivity analyses in supplementary materials.

Framework Analysis will be used to analyse qualitative data, adopting an iterative process of reading and annotating transcripts to identify salient themes, which will form the basis for comparisons between and within settings.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1440
• Est. completion date: June 30, 2022
• Est. primary completion date: June 30, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

For cases:

Inclusion Criteria:

• Age 18 to 64 years

• Currently resident in catchment area (primary residence)

• Presence of International Classification of Diseases 10th Revision (ICD-10) psychotic disorder, including substance-induced psychoses

• Not treated with antipsychotic medication for more than one continuous month prior to the start of initial case identification

Exclusion Criteria:

• Transient psychotic symptoms resulting from acute intoxication as defined by ICD-10

• Moderate or severe learning disability, as defined by ICD-10

• Clinically manifest organic cerebral disorder (e.g. infections, parasitic, toxic, cerebrovascular, epilepsy, brain injury), as defined by ICD-10

For controls

Inclusion Criteria:

• Age 18 to 64 years

• Currently resident in catchment area (primary residence)

• Same gender as index case

• Within 5 years of age of index case

Exclusion Criteria:

• Past or current ICD-10 psychotic disorder

• Moderate or severe learning disability, as defined by ICD-10

• Clinically manifest organic cerebral disorder (e.g. infections, parasitic, toxic, cerebrovascular, epilepsy, brain injury), as defined by ICD-10

For relatives:

Inclusion Criteria:

• Age 18 and above

• Relative or carer of a case who has consented to participate in the current study

Exclusion Criteria:

• Insufficient contact with case to provide information on family burden or mental health

Related Conditions & MeSH terms

• Mental Disorders
• Psychotic Disorders

Locations

Country	Name	City	State
India	Schizophrenia Research Foundation	Chennai	Tamil Nadu
Nigeria	College of Medicine, University of Ibadan	Ibadan	Oyo
Trinidad and Tobago	School of Medicine, The University of West Indies	Saint Augustine

Sponsors (6)

Lead Sponsor	Collaborator
King's College London	London School of Hygiene and Tropical Medicine, Medical Research Council, Schizophrenia Research Foundation (SCARF India), The University of The West Indies, University of Ibadan

Countries where clinical trial is conducted

India,  Nigeria,  Trinidad and Tobago, 

References & Publications (3)

Cohen A, Padmavati R, Hibben M, Oyewusi S, John S, Esan O, Patel V, Weiss H, Murray R, Hutchinson G, Gureje O, Thara R, Morgan C. Concepts of madness in diverse settings: a qualitative study from the INTREPID project. BMC Psychiatry. 2016 Nov 9;16(1):388. — View Citation

Morgan C, Hibben M, Esan O, John S, Patel V, Weiss HA, Murray RM, Hutchinson G, Gureje O, Thara R, Cohen A. Searching for psychosis: INTREPID (1): systems for detecting untreated and first-episode cases of psychosis in diverse settings. Soc Psychiatry Psychiatr Epidemiol. 2015 Jun;50(6):879-93. doi: 10.1007/s00127-015-1013-6. Epub 2015 Jan 29. — View Citation

Morgan C, John S, Esan O, Hibben M, Patel V, Weiss H, Murray RM, Hutchinson G, Gureje O, Thara R, Cohen A. The incidence of psychoses in diverse settings, INTREPID (2): a feasibility study in India, Nigeria, and Trinidad. Psychol Med. 2016 Jul;46(9):1923-33. doi: 10.1017/S0033291716000441. Epub 2016 Mar 28. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incident cases (untreated psychotic disorder)	Number of people with untreated psychotic disorder in the catchment area. Assessed using the Screening Schedule for Psychosis	During 2 year follow-up period
Primary	Clinical presentation of psychotic disorder according to SCAN	Assessed using Schedules for Clinical Assessment in Neuropsychiatry (SCAN). The SCAN aims to assess, measure and classify psychopathology and behaviour associated with major psychiatric diagnoses. It does not have minimum or maximum scores. Generally, scores of 0 to 3 are used to determine the presence and severity of a symptom (with 3 representing a worse outcome). Other higher scores (i.e. 5, 8 and 9) are used when there is no sufficient information to make an assessment.	At baseline
Primary	Change from baseline clinical presentation at 2-year follow-up according to SCAN	Assessed using Schedules for Clinical Assessment in Neuropsychiatry (SCAN). The SCAN aims to assess, measure and classify psychopathology and behaviour associated with major psychiatric diagnoses. It does not have minimum or maximum scores. Generally, scores of 0 to 3 are used to determine the presence and severity of a symptom (with 3 representing a worse outcome). Other higher scores (i.e. 5, 8 and 9) are used when there is no sufficient information to make an assessment.	Change from baseline clinical presentation at 2-year follow-up
Primary	Clinical presentation of psychotic disorder according to PANSS	Assessed using Positive and negative syndrome scale (PANSS), which includes the positive scale (7 items; minimum score = 7, maximum score = 49), negative scale (7 items; minimum score = 7, maximum score = 49) and general scale (16 items; minimum score = 16, maximum score = 112). Higher scores mean worse outcomes.	At baseline
Primary	Change from baseline clinical presentation at 2-year follow-up according to PANSS	Assessed using Positive and negative syndrome scale (PANSS), which includes the positive scale (7 items; minimum score = 7, maximum score = 49), negative scale (7 items; minimum score = 7, maximum score = 49) and general scale (16 items; minimum score = 16, maximum score = 112). Higher scores mean worse outcomes.	Change from baseline clinical presentation at 2-year follow-up
Primary	Psychiatric, medical and social history	Assessed using Psychiatric and Personal History Schedule (PPHS) baseline	At baseline
Primary	Change from baseline psychiatric, medical and social outcomes at 2-year follow-up	Assessed using Psychiatric and Personal History Schedule (PPHS) baseline and follow-up	Change from baseline psychiatric, medical and social outcomes at 2-year follow-up
Primary	Clinical course and outcome	Assessed using the WHO Life Chart, which measures participant's experiences during the follow-up period in the following areas: residence, work, symptoms and treatment	At 2-year follow-up
Primary	Baseline cognition	Assessed using Brief Assessment of Cognition (BACS) which includes six subtests: verbal memory (minimum score: 0, maximum score: 75), working memory (minimum score: 0, maximum score: 28), motor speed (minimum score: 0, maximum score: 100), verbal fluency (no minimum or maximum score), attention and speed information processing (minimum score: 0, maximum score: 110) and executive functions (minimum score: 0, maximum score: 22). Higher scores mean better outcomes.	At baseline and at 2-year follow-up
Primary	Change from baseline cognitive outcomes at 2-year follow-up	Assessed using Brief Assessment of Cognition (BACS) which includes six subtests: verbal memory (minimum score: 0, maximum score: 75), working memory (minimum score: 0, maximum score: 28), motor speed (minimum score: 0, maximum score: 100), verbal fluency (no minimum or maximum score), attention and speed information processing (minimum score: 0, maximum score: 110) and executive functions (minimum score: 0, maximum score: 22). Higher scores mean better outcomes.	Change from baseline cognitive outcomes at 2-year follow-up
Primary	Functioning and disability according to GAF	Assessed using Global Assessment of Functioning Scales (GAF) including symptom and disability scales (minimum score: 1, maximum score: 100). Higher scores mean better outcomes.	At baseline
Primary	Functioning and disability according to DAS	Assessed using the Disability Assessment Schedule (DAS). For outpatient participants: minimum score: 0, maximum score: 5; for inpatient: minimum score: 0, maximum score: 2. Higher scores mean worse outcomes.	At baseline
Primary	Change from baseline functioning and disability at 2-year follow-up according to GAF	Assessed using Global Assessment of Functioning Scales (GAF) including symptom and disability scales (minimum score: 1, maximum score: 100). Higher scores mean better outcomes.	Change from baseline functioning and disability at 2-year follow-up
Primary	Change from baseline functioning and disability at 2-year follow-up according to DAS	Assessed using the Disability Assessment Schedule (DAS). For outpatient participants: minimum score: 0, maximum score: 5; for inpatient: minimum score: 0, maximum score: 2. Higher scores mean worse outcomes.	Change from baseline functioning and disability at 2-year follow-up
Primary	Employment and marriage status	Assessed using MRC Sociodemographic Schedule	At baseline
Primary	Change in baseline employment and marriage status at 2-year follow-up	Assessed using MRC Sociodemographic Schedule	Change in baseline employment and marriage status at 2-year follow-up
Primary	Sociodemographic characteristics	Assessed using the Medical Research Council (MRC) Sociodemographic Schedule	At baseline
Primary	Changes in baseline sociodemographic characteristics at 2-year follow-up	Assessed using the Medical Research Council (MRC) Sociodemographic Schedule	Changes in baseline sociodemographic characteristics at 2-year follow-up
Primary	Place of residence	Assessed using Global Positioning System (GPS) coordinates	At baseline
Primary	Changes in baseline place of residence at 2-year follow-up	Assessed using Global Positioning System (GPS) coordinates	Changes in baseline place of residence at 2-year follow-up
Primary	Physical health outcomes according to WHO STEPS	Assessed using the WHO STEPS	At baseline
Primary	Changes in baseline physical health outcomes at 2-year follow-up	Assessed using the WHO STEPS	Changes in baseline physical health outcomes at 2-year follow-up
Primary	Baseline blood pressure	Assessed through blood pressure measurements using a sphygmomanometer	At baseline
Primary	Changes in baseline blood pressure at 2-year follow-up	Assessed through blood pressure measurements using a sphygmomanometer	Changes in baseline blood pressure at 2-year follow-up
Primary	Baseline lipids	Assessed using measures of total cholesterol, triglycerides and HDL cholesterol in blood samples	At baseline
Primary	Changes in baseline lipids at 2-year follow-up	Assessed using measures of total cholesterol, triglycerides and HDL cholesterol in blood samples	Changes in baseline lipids at 2-year follow-up
Primary	Baseline c-reactive protein	Assessed using blood samples	At baseline
Primary	Changes in baseline c-reactive protein at 2-year follow-up	Assessed using blood samples	Changes in baseline c-reactive protein at 2-year follow-up
Primary	Baseline presence of hepatitis C, malaria, dengue, chikungunya and anemia	Assessed using blood samples	At baseline
Primary	Changes in baseline presence of hepatitis C, malaria, dengue, chikungunya and anemia at 2-year follow-up	Assessed using blood samples	Changes in baseline presence of hepatitis C, malaria, dengue, chikungunya and anemia at 2-year follow-up
Primary	Baseline inflammatory markers	Assessed using blood samples	At baseline
Primary	Changes in baseline inflammatory markers at 2-year follow-up	Assessed using blood samples	Changes in baseline inflammatory markers at 2-year follow-up
Primary	Tuberculosis at baseline	Assessed using screen for tuberculosis	At baseline
Primary	Changes in baseline presence of tuberculosis at 2-year follow-up	Assessed using screen for tuberculosis	Changes in baseline presence of tuberculosis at 2-year follow-up
Primary	Medication regiment	Assessed using Medication Checklist	At baseline
Primary	Changes in baseline medication regiment at 2-year follow-up	Medication Checklist	Changes in baseline medication intake at 2-year follow-up
Primary	Baseline medication side effects	Assessed using Glasgow Antipsychotic Side-effect Scale (GASS)	At baseline
Primary	Changes in baseline medication side effects at 2-year follow-up	Assessed using Glasgow Antipsychotic Side-effect Scale (GASS)	Changes in baseline medication side effects at 2-year follow-up
Secondary	Major mood and psychotic disorders among relatives	Assessed using Family Interview for Genetic Studies (FIGS)	At baseline
Secondary	Achievement of developmental goals during early life	Assessed using Premorbid Adjustment Scale (PAS) which is comprised of five sections. Four of the five sections are rated twice. Minimum ratings: 0, maximum ratings: 6. Higher ratings mean worse outcomes.	At baseline
Secondary	Substance use	Assessed using Alcohol, Smoking and Substance Involvement Screening Test (ASSIST)	At baseline
Secondary	Changes in baseline substance use at 2-year follow-up	Assessed using Alcohol, Smoking and Substance Involvement Screening Test (ASSIST)	Changes in baseline substance use at 2-year follow-up
Secondary	Exposure to childhood trauma	Assessed using Childhood Trauma Questionnaire (CTQ). Comprised of five subscales each with a minimum score: 5, maximum score: 25. Higher scores mean worse outcomes.	At baseline
Secondary	Exposure to traumatic events according to HTQ	Assessed using Harvard Trauma Questionnaire (HTQ)	At baseline
Secondary	Changes in baseline exposure to traumatic events at 2-year follow-up according HTQ	Assessed using Harvard Trauma Questionnaire (HTQ)	Changes in baseline exposure to traumatic events at 2-year follow-up
Secondary	Exposure to traumatic events according to LoTE	Assessed using List of Threatening Events (LoTE)	At baseline
Secondary	Changes in baseline exposure to traumatic events at 2-year follow-up according LoTE	Assessed using List of Threatening Events (LoTE)	Changes in baseline exposure to traumatic events at 2-year follow-up
Secondary	Social support	Assessed using the Composite International Diagnostic Interview (CIDI) support networks module	At baseline
Secondary	Changes in baseline social support at 2-year follow-up	Assessed using the Composite International Diagnostic Interview (CIDI) support networks module	Changes in baseline social support at 2-year follow-up
Secondary	Social, health and economic burden on family/caregivers	Assessed using Family Burden Interview Schedule (FBIS). Comprised of 24 items. Each scored 0 to 3. Higher scores mean worse outcomes.	At baseline
Secondary	Change in baseline social, health and economic burden on family/caregivers at 2-year follow-up	Assessed using Family Burden Interview Schedule (FBIS). Comprised of 24 items. Each scored 0 to 3. Higher scores mean worse outcomes.	Change from baseline family burden at 2-year follow-up
Secondary	Help seeking and impact	Assessed using McGill Illness Narrative Interview (MINI) - qualitative	At any one-time point during the study period
Secondary	Genetic material	Assessed using blood samples	At baseline