Depression Clinical Trial
Official title:
Effectiveness of a Brief Manualized Intervention Managing Cancer and Living Meaningfully (CALM) Adapted to the Italian Cancer Care Setting. Study Protocol for a Randomized Controlled Trial
Background: Patients with advanced cancer suffer from a variety of psycho-social symptoms
that impair quality of life and may benefit from psychotherapeutic treatment. We describe
here the methodology of a randomized controlled trial to test the effectiveness of a novel
and brief semi-structured psychotherapeutic intervention, called Managing Cancer and Living
Meaningfully (CALM), originally developed in Canada and now cross-culturally tested in Italy.
Methods/Design: The study is a single-blinded randomized controlled trial with 2 conditions:
CALM intervention versus nonspecific supportive intervention (SPI) and assessments at
baseline, 3 and 6 months. The coordinating site is the Program on Psycho-Oncology and
Psychiatry in Palliative Care, University of Ferrara and Integrated Department of Mental
Health, S. Anna University Hospital, in Ferrara, Italy. Another centre from northern and
southern Italy will collaborate. Eligibility criteria include: ≥ 18 years of age; Italian
fluency; no cognitive impairment; and diagnosis of advanced cancer. The intervention consists
of 12 sessions , following the CALM manual and allowing for flexibility to meet individual
patients' needs. It is delivered over a 6-month period and provides reflective space for
patients (and their primary caregivers) to address 4 main domains: symptom management and
communication with health care providers; changes in self and relations with close others;
sense of meaning and purpose; and the future and mortality. The primary outcome is depression
and the primary endpoint is at 6 months. Secondary outcomes include demoralization,
generalized anxiety, death anxiety, spiritual well-being, quality of life, attachment
security, posttraumatic growth, communication with partners, and satisfaction with clinical
interactions.
Discussion: This trial is being conducted to determine the effectiveness of CALM in an
Italian cancer setting. The intervention has potential cross-national relevance and, if shown
to be effective, has the potential to be disseminated as a new approach in oncology to
relieve distress and promote psychological well-being in patients with advanced cancer.
The study is coordinated by the Program on Psycho-Oncology and Palliative Care, University of
Ferrara Northern Italy. Another centre from northern Italy will collaborate. The study is
designed as a single-blinded randomized-controlled trial with two arms. Participants in the
experimental group will receive the CALM intervention, while those in Control Group will
receive a supportive intervention, which is usual psycho-oncology care in our settings.The
primary outcome is depression. The primary endpoint is 6 months. Secondary outcomes include
demoralization, generalized anxiety, death anxiety, spiritual well-being, quality of life,
attachment security, posttraumatic growth, communication with partners, and satisfaction with
clinical interactions.The study has received approval from Ethical Committees.
Interventions:Patients in the experimental group will receive the CALM intervention, a
semi-structured psychotherapy designed for patients with advanced cancer. In this Italian
adaptation, CALM consists of 12 individual sessions (45-60 minutes each), instead of the
original 6 sessions. The sessions are delivered bimonthly over a period of 6 months.
The intervention covers four domains: 1) Symptom management and communication with health
care providers; 2) Changes in self and relations with close others; 3) Spiritual well-being,
sense of meaning and purpose; 4) Preparing for the future, sustaining hope and facing
mortality.
Non-manualized supportive psycho-oncology intervention (SPI):The Control group intervention
includes counseling, information, crisis intervention, which is the usual care intervention
provided in our center. As with CALM patients, SPI patients receive up to twelve sessions of
individual therapy during a period of 6 months.
Inclusion criteria are:18 years of age or more;fluency in Italian language; absence of
cognitive deficit documented in the clinical records;diagnosis of "wet" stage IIIB or IV lung
cancer; any stage of pancreatic cancer, stage III or IV ovarian and fallopian tube cancers,
or other stage IV gynecological cancer; and stage IV breast, genitourinary, gastrointestinal,
melanoma, sarcoma, or endocrine cancers (all with an expected survival of 12-18 months); a
score ≥10 at the Patient Health Questionnaire and/or ≥ 20 at the Death and Dying Distress
Scale. Exclusion criteria are: language barriers hindering psychotherapy;inability to commit
to the required 12 sessions; concomitant psychotherapy.
Randomization procedure:Study participants are randomly assigned to receive either CALM or
SPI. After obtaining informed consent , a research assistant includes patient's data on the
random allocation list and informs the PI's about treatment allocation (CALM or SPI). The
patient is not informed about treatment condition (CaLM or SPI).
Measures:The Patient Health Questionnaire (PHQ-9) is a 9-item measure of depression. It is
composed by nine items, reflecting DSM-IV criteria for major depression. A four-point Likert
scale scores from 0 (not at all) to 3 (nearly every day), with a cut-off score of ≥10
suggesting depression. For study purposes, two additional items assessing self-harm intention
and rating how difficult these symptoms have made it to do lead one's life, have been
included.The Demoralization Scale (DS) is a 24-item self-report tool assessing demoralization
components of loss of meaning and purpose, dysphoria, disheartenment and helplessness. Items
are scored on a five-point Likert scale ranging from 0 (never) to 4 (all the time). Low
levels of demoralization were indicated by a score 10, moderate demoralization by a score
11-36, and high demoralization by a score > 37.The Generalized Anxiety Disorder Questionnaire
(GAD-7) is a 7-item self-report instrument screening the severity of GAD symptoms. Items are
scored on a four-point Likert scale ranging from 0 (not at all) to 3 (nearly every day).
Scores ≤4 indicate absence of anxiety, scores from 5 to 9 suggest that mild anxiety is
present, and scores from 10 to 15 indicate moderate levels of anxiety. An eighth item rating
how difficult these symptoms have made it to lead one's daily life has been included. The
Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-SP)[v] is
a 12-item self-report tool, exploring spiritual well-being, in terms of sense of meaning,
faith and inner peace. Items are scored on a five-point Likert scale from 0 (not at all) to 4
(very much), with higher scores indicating a greater spiritual wellbeing.The Posttraumatic
Growth Inventory (PTGI) is a 21-item self-report measure of positive psychological changes
after traumatic events. It consists of four subscales: New Possibilities, Appreciation of
Life, Relating to Others and Spiritual Change. Items are scored on a three-point Likert scale
ranging from 0 (not at all) to 2 (very much) with higher scores indicating greater
post-traumatic growth.The Quality of Life at the End of Life-Cancer Scale (QUAL-EC) is a
self- report measure of quality of life in patients near the end of life. It originally
consists of four subscales: Symptom Control, Relationship with Health Care Providers,
Preparation for End of Life and Life Completion. For this study purposes, the symptom control
subscale is not included, thus only items 4-17 are used. Items are scored on a five-point
Likert scale ranging from 1 (not at all) to 5 (completely), with higher scores indicating
higher quality of life.The Death and Dying Distress Scale (DADDS), is a 15-item self-report
measure assessing specific concerns of advanced cancer patients about end of life, feeling a
burden to others and wasted opportunities. It is scored on a six-point Likert scale from 0
(no distress) to 5 (very much distress), with higher scores indicating higher death anxiety
and distress.The Experiences in Close Relationships Inventory Modified Short Form Version
(ECR-M16), is used in its 16-item self-report form to measure the attachment style. The scale
yields scores on two dimensions of attachment: avoidance and anxiety. Items are scored on a
seven-point Likert scale ranging from 1 (disagree) to 7 (agree), with a total sum score on
each subscale ranging from 16 to 56. Higher scores on both subscales indicate higher
attachment insecurity.The Memorial Symptom Assessment Scale (MSAS) [x]assesses the disease
symptom severity. The scale, in its shortened version (MSAS- short form), measures the
presence and severity of 28 common physical symptoms of cancer. Items are scored on a
five-point Likert scale ranging from 0 (not at all) to 4 (very much).
The Couple Communication Scale (CCS) is used for participants who have a partner. The 10-item
CCS taken from the PREPARE/ENRICH Inventory is concerned with an individual's feelings,
beliefs, and attitudes about the communication in his/her romantic relationship. Each item is
scored from 1 (strongly disagree) to 5 (strongly agree).
Intervention and control participants will complete the Clinical Evaluation Questionnaire
(CEQ) at 3 and 6-months. The CEQ is a seven-item self-report questionnaire which assesses the
amount of clinical benefit patients have experienced by from therapy at the time of the
assessment. Items are rated from 0 to 4, with 0 (no clinical benefit) and 4 (a great clinical
benefit).Satisfaction of patients will also be qualitatively assessed by inviting them to
share comments in a written form after completing CEQ questionnaire.
Assessment:At baseline (T0), participants provide demographics and medical and treatment data
using a standardized questionnaire and will complete all outcome measures, with the exception
of the CEQ. The PHQ-9 and DADDS are first administered to assess eligibility prior to study
entry, followed by the remaining baseline outcomes. Follow-up assessments on all outcomes are
collected at three months (T1) and six months (T2). The CEQ is administered only at three
months (T1) and six months (T2) as it is an evaluation of the intervention received to date.
At T2, participants will also be queried about their having remained blind (or not) to
randomization.
Statistical methods:To calculate the required sample size, we used a validated, manualized
online power and sample size calculator that is ideal for longitudinal multilevel designs,
GLIMMPSE [ ]. A total sample size estimate for our primary hypothesis, that the treatment
group (CALM) will demonstrate a greater higher improvement ind depressive symptoms (PHQ-9) at
follow-up periods, as compared to the control group (SPI), was derived with a target power of
80% and alpha of .05 and with estimated mean scores, with variability, and cross-time
correlations entered. For the primary hypothesis, the calculated total sample size is 124
patients (62 patients per treatment arm). To account for anticipated attrition while
maintaining the targeted power, we used the following equation to calculated an adjusted
sample size: N = N0 * (1 + DRP), where N0 = original estimated sample size required at
baseline; DRP = anticipated dropout rate across participants. For an anticipated completion
rate of 70% rate (30% dropout rate), the adjusted sample size for this attrition rate is N =
124 * (1 + .30) = 161.2. The adjusted sample size at baseline will therefore be 162, with 81
patients per treatment arm.
Statistical analyses will be carried out by using SPSS Statistics program. For the final
analyses we will use an intention-to-treat approach (ITT) and compare patients in the
assigned treatment arms. To test the pPrimary hypothesis : we hypothesize that mean
depression scores in the intervention arm will be lower than in the control arm at 3 and 6
months, . We will use multilevel modeling (MLM) with maximum likelihood estimation to conduct
the intent-to-treat analysis in testing hypotheses. MLM includes all participants, including
those with missing data, in model estimation and also accounts for both inter-center and
intra-center variability.To test for treatment-arm differences, we will compare the CALM and
SPI groups on the primary outcome of PHQ-9 scores and on the secondary outcomes at the
follow-up periods. This will entail the following set of MLM analyses:i)We will first test
the level-1 predictor of Time, coded for the primary hypothesis as a categorical variable
representing baseline and the 6-month follow-up period (primary endpoint). To code time for
tests of secondary hypotheses, the categorical time variable will include baseline and the
3-month (secondary endpoint) and 6-month follow-up periods. ii)Next, we will add the level-2
treatment-group main effect and the cross-level treatment group x time interactions to test
the hypothesized treatment-group differences at follow-up periods. Pairwise comparisons will
evaluate the treatment-group difference at each follow-up period.iii)We will finally test
whether the fixed effects in step ii change when any identified covariates are added to
control for their effects. As a sensitivity analysis, we will use multiple imputation to
examine the influence of missing values. Lastly, prior trial results suggest that there may
be arm differences in the processing of death-related distress such that individuals with
moderate death anxiety tend to be more responsive to the intervention than either those with
low death anxiety (approximately the lower third of the distribution) or those with high
death anxiety (the upper third). We will conduct a sub-analysis to confirm this effect, by
examining the effect of removing individuals with low and high death anxiety scores at
baseline (i.e., DADDS < 15), following the Canadian protocol.
We will also qualitatively analyze the participants' comments about CALM and SPI on the CEQ.
NVivo Plus software package will be used for the qualitative analysis of data.
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