healthmedicinet

Aim of the study

The main aim of this study is to test the effectiveness and cost-effectiveness of
a stepped-care intervention program for depression in adults delivered mostly by non-physician
PHCWs with medical and specialist supervision and support provided with the use of
mobile phones compared to usual care in a randomized controlled trial.

Design

This study is a two-arm parallel cluster randomized controlled trial comparing an
intervention package for depression in primary care based on a version of the mhGAP-IG
contextualized and adapted for the extant Nigerian health system to care as usual.
The unit of randomization is the primary care clinic. As the intervention is designed
to be delivered by clinic staff, the cluster randomized design was chosen in order
to reduce the potential risk of contamination within clinics.

Setting

The study is being conducted in Oyo State, Nigeria. The state has 33 local government
areas (LGAs), from which eleven LGAs (five urban and six rural) were selected for
the study. We included both urban and rural LGAs in order to capture the diversity
of the socioeconomic profile of the country and because access to medical treatment
differs substantially between these two types of setting, thus making the demonstration
of the utility of our program potentially more generalizable. Our sampling frame included
all the primary health care clinics (PHCCs) that have a full complement of primary
care workers and provide a broad range of clinical services in the eleven LGAs (n?=?97).
Of these, 52 provided only maternal and child health care and were excluded and 10
did not consent to participate. The remaining 35 were randomized to the two arms of
the study, 18 to intervention arm and 17 to the control arm.

Health care providers in these clinics consist of nurses, community health officers
and community health extension workers. Each of these categories of providers has
a minimum of two to three years of post-secondary education. Supervision for all the
clinics in an LGA is provided by one general practitioner who is designated as the
Primary Health Care Coordinator for the Local Government.

The study procedures were described to the supervising physicians in each of the LGAs
and to the matrons or facility managers in each of the clinics. Only clinics providing
explicit consent to participate were randomized into the trial.

Randomization

Eligible and consenting primary health care clinics were stratified by local government
area and allocated to intervention or control arm using a computer-generated random
number sequence. Allocation was conducted by one of the authors (AAM) using anonymous
codes for clinics and LGAs provided by other members of the research team, in order
to avoid any risk of selection bias.

Ethics and research governance

General information about depression is provided to all consecutive attendees in the
waiting area of the clinic by trained research staff, after which their permission
is sought for the screening interview. Those who screen positive (PHQ-9 score of 11
and above) have the full study protocol explained to them and willing participants
sign the consent form.

Full ethical approval to conduct STEPCARE was obtained from the University of Ibadan/University
College Hospital Joint Ethics Committee.

Adherence to Committee’s specifications and approved protocol is monitored by two
independent groups: a Data Monitoring and Ethics Committee (DMEC) and a Trial Steering
Committee (TSC). Both the DMEC and TSC conduct regular reviews of the field work,
have one annual scheduled face-to-face meeting and twice yearly teleconferences. The
role of the DMEC is to advise the TSC on issues relating to safety and ethical conduct
of the study while the TSC has the responsibility of providing overall oversight for
the study, including ensuring its implementation according to the approved protocol.
The day-to-day implementation of the study is co-ordinated by the Study Management
Team whose members include all the investigators, a Trial Manager and supervisors.
The team meets bi-monthly by teleconference and annually face-to-face.

Recruitment of participants and eligibility

Consecutive attendees at the selected PHCCs are approached while waiting to see the
health care providers and are screened for depression using the 9-item patient health
questionnaire (PHQ-9). Those who screen positive (PHQ-9 score 11 and above) are assessed
for eligibility and invited to take part in the study. All consenting adults patients,
aged 18 years and above with a score of 11 or more on PHQ-9 with confirmed DSM-IV
diagnosis of major depression (depression diagnosis is confirmed using the short form
of the Composite International Diagnostic Interview (CIDI) 16], 17] are eligible to participate. Patients are ineligible if there is an immediate need
for medical attention, they are pregnant or nursing mothers, are actively suicidal,
have a history of bipolar or psychotic disorder or of severe substance dependence.
Also ineligible are those who are unlikely to remain in the neighbourhood over the
following 12 months.

Treatment in the intervention arm

Eligible and consenting patients are handed their PHQ-9 score and directed to see
one of the trained PHCWs in the clinic. The PHCW takes further history to establish
duration of symptoms, presence of any emergency (medical emergency or suicidality)
and determines what intervention to administer.

The intervention incorporates components of the WHO mhGAP-Intervention Guide (MHGAP-IG)
for depression, contextualized and adapted for the Nigerian health system 18], 19], and Problem Solving Treatment (PST) as used successfully in other interventions
in LMIC 20] and in our pilot study 21]. The MHGAP-IG is designed to facilitate the recognition and management of a set of
priority mental, neurological, and substance use (MNS) disorders in non-specialist
settings. The depression module describes approaches for the recognition as well as
the pharmacological and non-pharmacological treatment of depression. Problem solving
approaches have proven to be successful in the treatment of common mental disorders
such as depression and anxiety 20].

The intervention is pragmatic, based on a stepped-care model, and is fully manualized.
It is designed to be delivered in three steps determined by the patient’s score on
the PHQ-9 and response to treatment (See Fig. 1). All interventions are carried out in the Yoruba language by health care providers
fluent in the language and experienced in practicing in the locality. The interventions
have been adapted to the local context and tested during a pilot study 21].

Fig. 1. Treatment flow chart

All individuals consenting to the trial receive step 1. In step 1, participants with PHQ-9 score between 11 and 14 receive only psychological
interventions delivered by the PHCWs while those with PHQ-9???15 at baseline are immediately
assessed with the aim of initiating antidepressant medication in addition to the psychological
treatment. Antidepressant medication is initiated following a discussion of the results
of the assessment of the patient by the PHCW with the supervising general physician,
using mobile phone. After 8 weekly sessions, all participants are re-assessed with
the PHQ-9 and those who have not shown much improvement or whose symptoms worsen (PHQ-9??50 %
of baseline score or ?11) are moved to step 2. Participants in step 2 who have not previously been on antidepressant medication
are reviewed in consultation with the GP with a view to initiating antidepressant
medication and those who are already on medication are similarly assessed by the GP
with a view to modifying medication regime. All participants who do not improve after
this step may have their cases discussed with a psychiatrist by the GP in the final
step 3 in the sequence covering up to 6 months. The manual provides full description of
each step and the required clinical decisions. At each visit, the PHCW asks structured
questions to identify participants at risk of suicide, or who develop adverse reactions
to medication. Such participants are flagged as an emergency and the GP is contacted
immediately for consultation. All supervision and consultations with doctors are provided
by mobile phones except when a face-to-face review is deemed necessary and feasible.

The psychological component of the intervention consists of psychoeducation, reactivation
of social network, and PST. This intervention is delivered in 8 weekly sessions to
all participants entering the program regardless of the need for medication. All sessions
are carried out face-to-face in the clinic. Each session lasts approximately 30-45 min
and are scheduled at times agreeable to both the patient and the PHCW. The initial
session is dedicated to psychoeducation in which the symptoms of depression, possible
causes and treatments are discussed. The following 5 sessions are focused on the basics
of PST by working with the patient to identify and explore solutions to difficulties/problems
they are currently facing. The PST in Session 6 is specifically dedicated to exploring
support through social networks and the last two sessions are about integrating it
all and preparing for the future.

The first line medication is amitriptyline, which non-physician primary care providers
in Nigeria are authorized to prescribe. Other antidepressants could be prescribed
by the GPs for patients who do not improve or have other contraindications to the
use of tricyclic antidepressants. PHCWs are expected to consult with the GP when PHQ-9
denotes severe depression (PHQ score of 15 and above), there is no improvement at
week 8 or in case of emergencies (e.g. suicidality or serious drug reaction).

Control arm

Participants in the control clinic receive ‘enhanced usual care’. Usual care is ‘enhanced’
by the training of the providers in this arm before the commencement of the trial
on the recognition and management of depression. Subjects who are recruited in the
control clinics are informed of their PHQ-9 scores and advised to show these to their
health care providers. The choice of treatment offered is left to the discretion of
the PHCW and consist of the usual services normally available in the clinics; these
include antidepressant medications, brief psychotherapeutic interventions, medical
consultations, or referral for specialty treatment. Although all these options are
potentially part of usual care, in reality, unstructured counselling is often all
a patient with recognized depression receives.

Training

Prior to recruitment of patients, providers in the intervention arm received training
on the recognition of depression, the delivery of the manualized intervention package,
how to obtain and document support and supervision received from the GP using mobile
phones. The training consisted of didactic lectures, clinical demonstrations and role
plays over a 3-day period. They had a further 2-day top-up training about a month
into the study to reinforce the acquired skills and review experience with implementation
of the intervention.

Training for the providers in the control arm was conducted separately. They received
a 2-day training on the identification and treatment of depression. This training
was based on the mhGAP-IG but without detailed PST training or guidelines and procedure
for obtaining structured support and supervision from physicians. That is, the providers
in the control arm were trained in the recognition and standard treatment of depression,
but not in the use of PST or the implementation of a stepped-care management approach
(see below).

Support and supervision in the stepped-care model

The components and tasks for each treatment session as well as the clinical decisions
and steps are detailed in manuals and charts provided to the PHCW and primary care
physicians. Mobile telephone lines were provided to each of the trained PHCW in the
intervention clinics and their supervising GPs and study psychiatrist. These mobile
phone lines are linked in a closed user group network where calls within the network
are free to facilitate consultation. All telephone reviews and consultations are on
as-needed basis, structured, and follow a flow-chart that proceeds from the PHCWs
through to the GP and to the psychiatrist.

Outcome measures

Primary

The primary outcome is the proportion of patients who recover from depression at 12 months
from entry to the trial. Recovery from depression is defined as a PHQ-9 score??6.

Secondary

Secondary outcomes are assessed at 6 and 12 months and consist of: 1) change in depression
symptoms at 6 months; 2) level of disability as assessed using the WHO Disability
Assessment Scale; 22] 3) Quality of life as measured using the WHO Quality of Life instrument 23] and 4) health care utilization, assessed with the Service Utilization Questionnaire
(SUQ), adapted for the purpose. The SUQ is derived from the Client Service Receipt
Inventory (CSRI) which is designed to collect information about the use and costs
of health and social services and other economic impacts such as time of work due
to illness 24], 25]. The unit costs or prices of these various resource inputs will be based on the results
of a costing analysis which we have conducted in a number of health facilities in
the setting of the trial.

We have used the scales included in this protocol in our previous studies as well
as during our pilot study and have found them to be acceptable to patients and sensitive
to change 21], 26], 27]. All outcome assessments are administered in face-to-face interviews at the respondents’
homes by trained interviewers using the Yoruba versions of the different instruments.
The Yoruba versions were derived by standard protocols of iterative back translations
and have been used in previous surveys with good psychometric properties. Outcome
assessors are not involved in delivering the intervention and are rotated between
PHCCs to collect data. We will seek to collect outcome data from every participant
not known to have died at the time of follow-up and who has not withdrawn consent,
regardless of compliance with allocated treatment.

Economic evaluation

We plan to carry out an economic evaluation. Using the SUQ, we will systematically
collect resource-use data, including any inpatient care, consultations with health
providers, use of drugs and laboratory tests, and also time and travel costs associated
with this service uptake. We will also collect information on the financing sources
for each of the categories in order to allow for an estimation of the extent of private,
out-of-pocket expenditures incurred by study subjects and their families. The unit
costs or prices of these various resource inputs will be derived by carrying out costing
analysis in a number of participating health facilities using data collection templates
and protocols previously developed and applied by us.

Since depression and associated disability outcomes for the stepped care intervention
are also expected to improve significantly, the intervention will ‘dominate’ usual
care (i.e. better outcomes, less cost). Such a hypothesis negates the need for a power
calculation. If, however, costs turn out to be higher in the intervention group, bootstrapped
incremental cost-effectiveness ratios for PHQ-9 depression and WHO-DAS disability
scores level will be derived. Using the results of the Nigerian sample of the WHO
multi-country survey study on health and health system responsiveness to convert WHO-DAS
summary score to a health state preference measure, we will also construct Quality
Adjusted Life Years (QALYs) for both groups, thereby allowing comparison of this intervention
with other evaluations undertaken in Nigeria and elsewhere. Whether point estimates
demonstrate dominance or not, results will be plotted on a cost-effectiveness plane
and presented as cost-effectiveness acceptability curves in order to show the probability
of the intervention being cost-effective at a range of ‘willingness-to-pay’ threshold
levels. We will conduct sensitivity analysis to take account of uncertainty and imprecision
in the measurements, including multiple imputation models for missing values.

Sample size and power calculation

Previous studies have shown that low to moderate intensity treatment for depression
yields effect sizes on a variety of questionnaire-based outcomes of about 0.33 standard
deviations, and about 50 % relative advantage in recovery rate compared to usual care
28]. Experience from our previous PHC studies as well as from the control arm of the
Chilean trial suggest a recovery rate of about 30 % for major depression with no active
treatment and about 70 % with treatment 29]. For our sample size estimation, we sought to detect an absolute difference of 18
percentage points (41 % recovery in control and 59 % in intervention groups respectively)
at 12 months, a difference that we think is both plausible for this type of intervention
and would promote changes in practice. We assumed an intra-cluster correlation coefficient
(ICC) of 0.05 based on pilot study data, and collection of the primary outcome for
80 % of participants. The uninflated sample size requires 131 per arm for analysis
to detect a difference of 59 % vs 41 % (equivalent odds ratio?=?2.1) with 80 % power
at the two-sided 5 % alpha level. We aimed to recruit 90 individuals per clinic. With
72 per cluster available for the primary analysis and an ICC of 0.05, the design effect
is 4.55, giving a total number required for analysis of 1190. We therefore aimed to
recruit 90 individuals from each of 16 clinics initially. As participant recruitment
was slower than anticipated, in March and November, 2014 we recruited and randomised
a further 19 clinics, giving a total of 35 in the study. Participant recruitment started
December 2013 and is still ongoing.

Data analysis

Individual data is collected and stored electronically using palmtops programmed to
capture information directly from respondents. This is to ensure accuracy and security
of data collection. All data are kept anonymously using codes to identify individuals.
Data is downloaded from palmtops to desktops located in the central office in Ibadan
where it will be cleaned and stored. These datasets do not contain the allocation
status of the participants which is kept as a separate file and only for the trial
statistician. Access to the datasets is possible for members of the research team
through a password-protected entry.

A full statistical analysis plan will be developed before any data are analyzed. The
analysis and presentation of the trial will be in accordance with CONSORT guidelines
for cluster randomized trials 30], 31]. The primary approach for comparative analyses will be to analyze participants as
randomized without imputation of missing data, and with due emphasis placed on confidence
intervals for the between-arm comparisons. We will use descriptive statistics to assess
balance between the trial arms at baseline for both clinic and individual participant
characteristics. In order to take appropriate account of the hierarchical nature of
the data, we will use multivariable mixed effects regression models to estimate recovery
from depression at 12 months for intervention group versus control, adjusting for
baseline depression and LGA as a stratification variable. In a secondary analysis,
we will further adjust for any variables that were imbalanced between trial arms at
baseline. These analyses will be repeated for secondary outcomes. We will conduct
sensitivity analyses to assess the potential effect of missing data, and will investigate
the effect of adherence with the intervention. We will investigate whether between-group
differences vary over time using data from all follow-up visits in repeated measures
analyses.

We will investigate whether there is any differential effect of the intervention according
to baseline symptom severity (PHQ-9 score 16, ?16) and duration (?3 months, 3 months)
by including appropriate interaction terms in the primary regression model. Since
the trial is powered to detect overall differences between groups rather than interactions
of this kind, the results will be interpreted with due caution.

Data analysis will be conducted once all follow-up is complete. There are no planned
interim analyses.