SOLIDARITY Finland Long-COVID (Remdesivir Long-term Follow-up Study of COVID Patients)

The SOLIDARITY Finland Long-COVID is the long-term follow-up of the remdesivir sub-study of
the SOLIDARITY Finland. (Following the WHO core protocol with local adjustments, the
SOLIDARITY Finland is an adaptive, randomized, open-label clinical trial evaluating the
safety and efficacy of possible therapeutic agents in hospitalized adult patients diagnosed
with COVID-19.)

Study population Adult patients with confirmed SARS-2-CoV-2 admitted to the hospital ward or
the intensive care unit (ICU) were included. Adult hospital patients, with definite COVID-19
and, as per the responsible doctor, no contraindication to the study drugs were entered into
the online electronic data collection system and randomly allocated between the local
standard of care alone or local standard of care plus remdesivir (daily infusion until
discharge or up to ten days). Between July 2020 and January 2021, 208 patients were recruited
from 13 hospitals, of which 114 were randomized to receive remdesivir plus usual care and 94
to receive usual care only. (These patients (if alive; n=202 or less) will be invited to
participate in the SOLIDARITY Finland Long-COVID.) During patient recruitment at the hospital
phase of the study, the following data was collected: 1) hospital and randomizing doctor; 2)
confirmation that patient has provided consent, 3) patient identifiers, age, and sex, 4)
major comorbidities, 5) COVID severity.

Consent:

All patients have already consented to SOLIDARITY Finland (in-hospital study). In the
SOLIDARITY Finland Long-COVID, patients will receive, by mail, an information letter, consent
form, and questionnaires. The mail will be sent three days before the anniversary of the
randomization day during hospitalisation. They may reply by i) sending back the completed
documents, ii) scheduling a phone call with an investigator for an interview, or iii)
declining participation. If the patient does not reply in 14 days (from the day the
investigators sent the questionnaire to the patient), the investigators will send one
reminder by mail and, if there will not be a reply, then the investigators will approach the
patient via telephone at around 10 days from the reminder mail. The phone call will be
attempted twice: during and after office hours. If the patient will not answer the phone, the
investigators will also send a text message to inform them about the reason for our attempted
phone call.

Questionnaire (symptoms and characteristics):

Our multidisciplinary team of clinicians, methodologists, and patient partners developed a
questionnaire that records basic patient information. This will include i) date of completing
the questionnaire, ii) age, iii) height and weight, iv) smoking status (never, ex-smoker,
current smoker), v) possible comorbidities, and whether diagnosed before or after
COVID-19-infection (obstructive sleep apnea, stroke, coronary artery disease, diabetes,
hypertension, cancer, and any psychiatric disease), vi) employment (student, unemployed,
employed, sickness allowance, retired), vii) working capability in comparison to the
pre-COVID-19 state, viii) physician visits due to symptoms associated with COVID-19, ix)
physician-diagnosed long-COVID-19 syndrome. Questionnaires will also document long-term
symptoms. Relevant long-COVID-19 -symptoms (in total 20) were identified from recent
publications and review articles. This same questionnaire will be used at one and two years.
Exertional and cardiopulmonary symptoms potentially related to COVID include fatigue,
postexertional malaise, dyspnea during exercise, chest discomfort, palpitations, cough, and
respiratory mucous discharges. Main neuropsychiatric symptoms potentially related to COVID
include generalized fatigue, attention and memory deficits, sleeping difficulties, depression
and anxiety, dizziness, and even sensory disturbances such as paresthesias and changes in
taste or smell perceptions. Other commonly encountered symptoms potentially related to COVID
include widespread pains (muscle and joint pains, headache), skin rash, nausea, and fever.
The burden from each individual symptom is an ordinal variable and will be graded from 0 to
3, where 0 represents no symptom, 1 represents mild bother, 2 moderate bother, and 3 severe
bother due to the symptom. Dyspnea is assessed in accordance with the Modified Medical
research council dyspnea scale (mMRC) from 0 to 4, where 0 represents dyspnea only with
strenuous exercise, and 4 the presence of dyspnea even with mild physical activity, e.g.,
dressing clothes. To capture the dimensions of recovery, the investigators will use the Core
Outcome Measure for Recovery, which has been recommended for use in COVID-19 research.

Quality of life:

The investigators have obtained permission from EuroQol to use the EQ-5D-5L questionnaire to
record the patient's QoL. EQ-5D-5L assesses the domains of mobility, self-care, usual daily
activities, general pain/discomfort, anxiety/depressions, and an overall impression of
health. The first five domains are graded from 1 to 5, while the last uses the visual
analogue scale from 0 to 100. Due to our multiethnic patient population, the questionnaires
have been translated in the following languages: Albanian, Arabic, English, Estonian, Farsi,
Finnish, Russian, Somali, and Swedish. The above-mentioned questionnaire (Finnish language
version as the original) has also been translated into these languages.

Data security and future use of data:

Patient information will be encrypted and held securely by the Sponsor. Those analyzing it
will use only pseudonymized data, and no identifiable patient details will appear in
publications. Data from questionnaires will also be analyzed using pseudonymized data. The
investigators have taken care to limit the questions to necessary and clinically relevant
aspects related to long-COVID.

UPDATE 02.02.2022:

Primary outcomes will comprise the following:

1. EQ-VAS

2. EQ-5D-5L, summary

3. Does the patient feel recovered from COVID-19-infection at one year or not? (question
no. 10)

4. Fatigue (questionnaire, question no. 14)

5. Exertional dyspnea (question no. 12)

To avoid problems related to multiple testing, the trial analysis will be focused on the five
most relevant outcomes (listed above). This decision was done before examining the
accumulated data, and by consulting statistical experts neither who had seen study data.

Variables collected via questionnaire:

i) Symptoms: 20 symptoms are measured as follows; each range from 0 to 3 (0 = No symptom. 1 =
Symptom exists and causes small bother. 2 = Symptom exists and causes moderate bother. 3 =
Symptom exists and causes severe bother.) ii) QoL: Using the EQ-VAS and EQ-5D-5L to compare
domain-specific scores between the two treatment arms.

Additional variables (at 1 or 2 years; depending on future funding and ethical approval
decisions; currently the study has ethical approval for long-COVID and quality of life
assessments only):

- Registry data: (UPDATE 02.02.2022) Mortality data with dates are obtained from Digital
and Population Data Services Agency during early spring 2022. Later, underlying causes
of death will be obtained from Statistics Finland and classified according to the
International Statistical Classification of Diseases and Related Health Problems, 10th
revision). In line with the Finnish regulations, any consent will not be required from
the study patients to acquire information on their census data, vital status, and causes
of death for registry research purposes. Comorbidity will be obtained from Finnish
Institute for Health and Welfare THL. These will be performed through linkage the
patient national identification number to registry records. This study is unlikely
well-powered to measure changes in mortality; however, being aware of the vital status
is important for the overall follow-up of study participants.

- Lung tests are also planned. Spirometry parameters are continuous variables as absolute
values (liters = L; liters per second = L/s), percentage of reference values, and
z-values. These include VC, FVC, FEV1, FEV1/VC, peak expiratory flow (PEF), the maximal
expiratory flow at 50 % (MEF50), and the forced expiratory time (FET). Spirometry will
be performed with a bronchodilator test to assess the changes between baseline and after
bronchodilation. Diffusing capacity parameter DLCO is a continuous variable with
ml/min/mmHg as the unit.

- Genome sequence analyses are also planned to identify potential single-nucleotide
polymorphisms that would associate with long-COVID symptoms and the effect of
remdesivir.

Subgroup analyses:

For the primary outcomes, a priori planned subgroup analysis will be performed for whether
the patient needed oxygenation at hospital admission (the investigators hypothesize that the
treatment effect is larger for those without extra oxygen than those with extra oxygen at
hospital admission).

Comparisons between the two treatment arms will be performed as follows:

- Descriptive statistics: Descriptive statistics will be presented with numbers and
percentages for categorical variables and means, standard deviation, and range for
continuous variables. In the case of clearly skewed continuous variables, they will be
presented with median, interquartile range (25th and 75th percentiles), and range.
Demographics and baseline characteristics will be presented with descriptive statistics
without any hypothesis testing.

- Continuous variables will be subject to repeated measures mixed models or appropriate
non-parametric alternatives.

- Binary response variables will be analyzed using logistic regression (possibly adjusting
for within-subject dependencies by generalized estimating equations or mixed models) or
chi-square/Mantel-Haenszel tests.

- If missing data is regarded as having a significant effect on the conclusions of the
trial, sensitivity analyses with different methods for handling missing data will be
included. The differences between respondents and non-respondents will be assessed using
available baseline variables.

Statistical analyses in more detail:

1. EQ-VAS

- Mann-Whitney test, when the treatment arm is the only variable.

- Regression analysis to adjust possible imbalances. Linear regression, if VAS scores
are not concentrated around either extreme of the scale.

2. EQ-5D-5L, summary.

- Proportions of respondents in both groups by categories (Mobility, Self-Care, Usual
Activities, Pain/Discomfort, Anxiety/Depression).

3. Does the patient feel recovered from COVID-19-infection at one year or not? (question
no. 10)

4. Fatigue (questionnaire, question no. 14)

- Logistic regression analysis. "No symptom" and "Mild symptoms" will be analyzed
together against "Moderate symptoms" and "Severe symptoms".

5. Exertional dyspnea (question no. 12) - Logistic regression analysis. mMRC categories 0
and 1 will be analyzed together against categories 2-4.