INTRODUCTION Around 20% of people with COVID-19 becomes seriously ill with pneumonia and
multi-organ failure, requiring hospital admission to relieve the symptoms and reduce
mortality. To avoid any spreading of the virus, hospitalized COVID-19 patients are isolated.
Thus, patients hospitalized with COVID-19 are limited in their social support and their only
in-person contact is with healthcare staff in full personal protective equipment. Several
studies highlight that isolation due to infection may have negative psychological
implications. Moreover, Patients with confirmed or suspected COVID-19 may experience fear of
the consequences of the infection. A high prevalence of persistent mental health problems has
been found among patients during infectious disease outbreaks such as the 2003 outbreak of
Severe Acute Respiratory Syndrome (SARS). Researchers and policy makers have highlighted that
the psychological impact of the COVID-19 pandemic must be recognized alongside the physical
symptoms for all those affected. Moreover, evidence-based evaluations and mental health
interventions targeting hospitalized COVID-19 patients and their relatives are at present
lacking. If left untreated, these psychological symptoms may have long-term health effects on
patients and require treatment adding to the cost burden of managing the illness.

OBJECTIVE The objective of this project is to test the efficacy of a minimal
psychoeducational intervention versus standard of care at discharge for reducing symptoms of
anxiety in hospitalized patients during the COVID-19 outbreak

METHODS Design This is a Randomized Controlled Trial (RCT) among hospitalized COVID-19
patients.

Hypothesis The primary hypothesis is that a minimal psychological intervention will reduce
anxiety as assessed by the Hospital Anxiety and Depression Scale (HADS) subscale for anxiety
(HADS-A) by 1.5 points from baseline to follow-up 1 month after discharge from hospital. The
estimated decrease in HADS-A is based on the clinically important difference found in
patients with COPD and isolation studies.

Study population Patients will be recruited from the Department of Infectious Diseases and
the COVID-19 isolation wards at Copenhagen University Hospital, Hvidovre; one of the major
hospitals treating COVID-19 patients in Denmark.

Eligible patients are consecutively identified at time of admission. Included patients are
randomized 1:1 to either a psychoeducational intervention or standard care delivered at
discharge.

Sample size The primary outcome of interest is the intra-individual differences in HADS-A
scores between baseline and follow-up 1 month post discharge. The design is paired with a
power of 0.80 and an α at p=0.05. To identify a difference of 1.5 points, which is the
minimal clinically important difference based on COPD and isolation studies, with an SD of
2.5 points, 25 patients are required in each group. Since the trial population consists of
severely ill patients with high morbidity and mortality rates 2, approximately 30% of the
sample are estimated to drop out. Thus, the RCT study requires 66 patients, with 33 in each
group.

Intervention at discharge Patients randomized to the intervention group will receive a
minimal psychoeducational intervention just prior to discharge from the hospital. The goal of
the intervention is that patients will be prepared and learn to interpret and react to
physical and psychological symptoms that are related to recovering from a COVID-19 infection.
The intervention consists of both written and verbal information. While both the written and
verbal information will be primarily targeted the patient, the role of relatives and their
possible reactions will be part of the dialogue. A manual describing the content and
procedures of the intervention will be developed to ensure that the intervention is both
replicable and transparent. The intervention has a planned duration of 30 minutes and will be
conducted by a designated study affiliated researcher, who has a background in healthcare
(i.e. nurse or medical doctor).

Standard of care at discharge Standard of Care at discharge of patients with COVID-19 from
hospital is to inform the patients whom to contact in case of worsening of the physical
condition, such as increasing e.g. shortness of breath, and of precautions regarding further
isolation to avoid infection of household and other contacts, if relevant. Information
regarding the patient´s psychological condition is not part of a standard conversation at
discharge.

Blinding Due to the nature of the intervention, the RCT trial is not blinded, but the outcome
measures are masked for health professionals and staff until the end of the study.

Data collection Data is collected using standardized questionnaires at four timepoints;
baseline completed within 48 hours after admission (T0), at discharge, but prior to
intervention (T1), 1 month (T2), 3 months (T3), and 12 months (T4). Patients will answer the
questionnaires electronically in REDCap© or via phone interview conducted by a study nurse or
medical student. Clinical data is collected from the medical records and entered into the
REDCap© database.

The following internationally well validated PROMs will be used to assess mental
health/distress:

- Anxiety and depression will be assessed using the Danish version of the HADS. The
primary outcome in the RCT study is anxiety measured by HADS-A.

- Perceived stress is measured using the Perceived Stress Scale - 10 item (PSS-10).

- Harvard Trauma Questionnaire (HTQ) is used to assess subjective distress caused by
traumatic events.

- Health related quality of life is measured by SF-12, a short version of the Medical
Outcomes Study (MOS) 36-item Short-Form Health Survey SF-36.

Sociodemographic and clinical variables The following demographic and clinical data are
collected from the patients records: age, gender, marital status, residence in nursing home,
medicine, smoking status, BMI, previous history of psychiatric illness, physical symptoms,
and clinical parameters such as Temperature (>/> 38C); demand of oxygen support (< 5 litres
O2/minute; 5-10 litres O2/minute; >10-30 O2/minute or need for mechanical ventilation).
Biochemical parameters (Hemoglobin, White Blood Cell (WBC) count, lymphocyte count, Lactate
Dehydrogenase, Alanine Amino Transferase (ALT), CRP). Length of hospital stay is collected at
discharge. Information regarding contact to general practitioner and current psychological
treatment outside of the study is collected during follow-up.

Statistical analysis Descriptive statistics of demographic characteristics at baseline (T0)
will be computed. The primary analysis for the RCT study will be performed on the basis of
the intention-to-treat principle. Baseline data for the two groups will be compared with
Student's t test, the chi-square test, or nonparametric tests. To analyse within group
differences in outcome scores, a Student´s t test or Wilcoxon rank-sum test will be used. A
mixed regression model will be used to assess the change within-group and between groups over
time. The co-variables included in the models will be chosen based on an a priori hypothesis,
the bivariate analysis and clinical relevance. Analyses will be performed using the STATA 13
software and in collaboration with an experienced statistician. All reported p-values are
two-sided using a significance level of 0.05.

ETHICAL CONSIDERATIONS The study has been approved by the Danish Data Protection Agency
[P-2020-349]. The national Health Research Ethics Committee has assessed the intervention as
not being a significant biomedical intervention [jr. nr. 20025879]. All participating
patients will provide written informed consent before any data collection.

TIME SCHEDULE This is a two-year study initiated as soon as possible and no later than mid
April 2020.

DISSIMINATION Publication of positive, neutral or negative results in international,
peer-reviewed journals will be sought. In addition, results will be communicated at relevant
scientific meetings and conferences.

PERSPECTIVE The results from this study have a number of important potential implications.
First, by quantifying the magnitude of psychiatric symptoms among hospitalized COVID-19
patients, potential risk factors associated with these symptoms can be identified. Second,
there is a need to develop and test the efficacy of minimal psychological intervention for
reducing psychiatric morbidity among COVID-19 patients. Providing psychological treatment and
support may reduce the burden of comorbid mental health conditions both short and long-term.
The challenge is to provide mental health services in the context of patient isolation.
Hence, the intervention is designed to give healthcare professionals an instrument that is
clinically applicable and easy to implement even in isolated patients. Finally, the
longitudinal design of the study capturing experiences over time, can be used to identify
when in the trajectory psychological interventions are most needed.