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

• ClinicalTrials.gov Identifier: NCT04978259
• Recruitment Status: Recruiting
• First Posted: July 27, 2021
• Last Update Posted: July 15, 2022
• Sponsor: Clinical Urology and Epidemiology Working Group
• Collaborators: University of Helsinki; World Health Organization; Helsinki University Central Hospital; Hyvinkää Hospital; Kanta-Häme Central Hospital; Kuopio University Hospital; Oulu University Hospital; Porvoo Hospital; Seinajoki Central Hospital; Mikkeli Central Hospital; Tampere University Hospital
• Information provided by (Responsible Party): Kari Tikkinen, Clinical Urology and Epidemiology Working Group

Tracking Information

• First Submitted Date: July 20, 2021
• First Posted Date: July 27, 2021
• Last Update Posted Date: July 15, 2022
• Actual Study Start Date: July 24, 2021
• Estimated Primary Completion Date: February 28, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 19, 2022)

• EQ-VAS [ Time Frame: 1 year ]
  EQ-VAS is a patient-reported outcome measure of quality of life on a scale from 0 to 100. The minimum scores mean a worse outcome.
• EQ-5D-5L [ Time Frame: 1 year ]
  Quality of life measure of five domains, including mobility, self-care, usual activities, pain/discomfort and anxiety/depression.
• Recovering from COVID-19 infection [ Time Frame: 1 year ]
  Question: How do you feel you have recovered from the COVID-19 infection you had one year ago? Five options from "fully recovered" to "not recovered at all"
• Fatigue [ Time Frame: 1 year ]
  The presence of fatigue as: 0 = no fatigue, 1 = mild fatigue, 2 = moderate fatigue, and 3 = severe fatigue.
• Exertional dyspnea [ Time Frame: 1 year ]
  mMRC scale measures the degree of disability that breathlessness poses on everyday activities on a scale from 0 to 4.
• Long-COVID symptoms [ Time Frame: 1 year ]
  Infection affected quality of life in the last month as: 0 = No symptoms of infection, 1 = Slight harm, 2 = Moderate harm, 3 = Severe harm

Original Primary Outcome Measures (submitted: July 22, 2021)

• Long-COVID symptoms [ Time Frame: At one year from hospital admission ]
  Specific questionnaire for symptoms and their severity.
• Long-COVID symptoms [ Time Frame: At two years from hospital admission ]
  Specific questionnaire for symptoms and their severity.
• Quality of life (QoL) [ Time Frame: At one year from hospital admission ]
  EQ-5D-5L questionnaire assesses the following domains: 1. Mobility; 2. Self-care; 3. Usual activities; 4. Pain and discomfort; 5. Anxiety and depression; 6. Visual analogue scale of subjective perception of overall health. Questions 1-5 are ordinal variables and the trouble severity has five degrees of severity from no trouble to the most extreme form of trouble. Question 6 is a VAS scale from 0-100, where 0 represents the worst and 100 the best possible overall state of health.
• Quality of life (QoL) [ Time Frame: At two years from hospital admission ]
  EQ-5D-5L questionnaire assesses the following domains: 1. Mobility; 2. Self-care; 3. Usual activities; 4. Pain and discomfort; 5. Anxiety and depression; 6. Visual analogue scale of subjective perception of overall health. Questions 1-5 are ordinal variables and the trouble severity has five degrees of severity from no trouble to the most extreme form of trouble. Question 6 is a VAS scale from 0-100, where 0 represents the worst and 100 the best possible overall state of health.

Current Secondary Outcome Measures (submitted: April 19, 2022)

• EQ-VAS [ Time Frame: 2 year ]
  EQ-VAS is a patient-reported outcome measure of quality of life on a scale from 0 to 100 The minimum scores mean a worse outcome.
• EQ-5D-5L [ Time Frame: 2 year ]
  Quality of life measure of five domains, including mobility, self-care, usual activities, pain/discomfort and anxiety/depression.
• Recovering from COVID-19 infection [ Time Frame: 2 year ]
  Question: How do you feel you have recovered from the COVID-19 infection you had one year ago? Five options from "fully recovered" to "not recovered at all"
• Fatigue [ Time Frame: 2 year ]
  The presence of fatigue as: 0 = no fatigue, 1 = mild fatigue, 2 = moderate fatigue, and 3 = severe fatigue.
• Exertional dyspnea [ Time Frame: 2 year ]
  mMRC scale measures the degree of disability that breathlessness poses on everyday activities on a scale from 0 to 4.
• Long-COVID symptoms [ Time Frame: 2 year ]
  Infection affected quality of life in the last month as: 0 = No symptoms of infection, 1 = Slight harm, 2 = Moderate harm, 3 = Severe harm

• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: April 19, 2022)

• Mortality [ Time Frame: Long-term at one year ]
  Obtiained from health care registries
• Incidence of comorbidity [ Time Frame: Long-term at one year, obtained from registries ]
  Obtiained from health care registries
• Lung function [ Time Frame: 2 years post-discharge ]
  Spirometry: VC, FVC, FEV1, FEV1/VC, peak expiratory flow (PEF), the maximal expiratory flow at 50 % (MEF50), and the forced expiratory time (FET)
• Lung function [ Time Frame: 2 years post-discharge ]
  Lung diffusion capacity: Diffusing capacity parameter DLCO is a continuous variable with ml/min/mmHg as the unit.
• Lung function [ Time Frame: 2 years post-discharge ]
  6-minute walking test
• Whole-genome sequencing [ Time Frame: 2 years post-discharge ]

Original Other Pre-specified Outcome Measures (submitted: July 22, 2021)

• Mortality [ Time Frame: Long-term at one year ]
  Obtiained from health care registries
• Incidence of comorbidity [ Time Frame: Long-term at one year, obtained from registries ]
  Obtiained from health care registries
• Lung function [ Time Frame: 2 years post-discharge ]
  Spirometry
• Lung function [ Time Frame: 2 years post-discharge ]
  Lung diffusion capacity
• Lung function [ Time Frame: 2 years post-discharge ]
  6-minute walking test
• Whole-genome sequencing [ Time Frame: 2 years post-discharge ]

Descriptive Information

• Brief Title: SOLIDARITY Finland Long-COVID (Remdesivir Long-term Follow-up Study of COVID Patients)
• Official Title: Long-term Follow-up of a Randomized Multicenter Trial on Impact of Long-COVID in Hospitalized COVID-19 Patients

Brief Summary

SOLIDARITY Finland Long-COVID trial assesses the effects of remdesivir + standard of care (SoC) vs. only SoC on long-COVID symptoms and quality of life (QoL) using questionnaires at one and two years post-discharge.

Objectives i) Long-COVID symptoms

• To investigate the effect of remdesivir (vs. SoC) on the occurrence of symptoms that have been associated with the long-COVID syndrome. The questionnaires will take place 1 and 2 years after the hospital admission.
• The symptom questionnaire - that will be completed by patients at one and two years - measures basic patient information (age, height, weight, smoking status, major comorbidity, and working status) and a wide variety of potential long-COVID-symptoms and their bother (1. Fatigue; 2. Attention deficits; 3. Memory problems; 4. Sleeping difficulties; 5. Depressive mood; 6. Anxiety; 7. Dizziness; 8. Headache; 9. Tinnitus; 10. Paresthesias; 11. Changes in taste/smell perceptions; 12. Postexertional malaise; 13. Palpitations; 14. Chest discomfort; 15. Nausea; 16. Skin rash; 17. Joint aches; 18. Muscle pains; 19. Continuous cough; 20. Respiratory tract mucous discharges) in remdesivir and usual care arms

ii) Quality of life

• EQ-VAS: to compare patients' quality of life in remdesivir and usual care arms.
• EQ-5D-5L questionnaire assesses the following domains: 1. Mobility; 2. Self-care; 3. Usual activities; 4. Pain and discomfort; 5. Anxiety and depression; 6. The VAS of subjective perception of overall health.

Additionally (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):

• The Finnish healthcare registries (Statistics Finland Mortality Database and the HILMO Care Register for Health Care) will be used to estimate long-term mortality and incidence of major comorbidity in remdesivir and usual care arms
• Lung function will be assessed using spirometry and diffusing capacity, as well as the six-minute walk test (6 mwt) in remdesivir and usual care arms
• Whole-genome genotyping will be performed for a genome-wide association study to investigate genetic correlates of long-COVID-19 -symptoms in remdesivir and usual care arms

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)

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Covid19

Intervention

Drug: Remdesivir

Intravenous remdesivir during hospital stay up to 10 days in addition to standard care.

Study Arms

• Experimental: Standard of care plus remdesivir
  Local standard of care plus daily remdesivir infusion for up to 10 days (or until discharge)
  Intervention: Drug: Remdesivir
• No Intervention: Standard of care
  Local standard of care

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 22, 2021): 202
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2023
• Estimated Primary Completion Date: February 28, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Alive patients who attended the SOLIDARITY Finland remdesivir sub-study

Eligibility criteria for SOLIDARITY Finland remdesivir -study:

Inclusion criteria:

• Adult patients, 18 years and older
• Laboratory-confirmed SARS-CoV-2 infection
• Admitted to the hospital ward or the intensive care unit (ICU)
• Patient provides written informed consent prior to initiation of the study OR close relative/legal representative provides written informed consent prior to initiation of the study according to the presumed will of the patient when patient is unable to give consent.
• No anticipated transfer within 72 hours to a non-study hospital

Exclusion Criteria:

• Severe co-morbidity with life expectancy <3 months according to investigators assessment
• ASAT/ALAT > 5 times the upper limit of normal
• Acute co-morbidity within 7 days before inclusion such as myocardial infarction or unstable angina pectoris (not including troponin elevation due to infection)
• Pregnancy or breast feeding
• Any reason why, in the opinion of the investigators, the patient should not participate
• Subject participates in a potentially confounding drug or device trial during the course of the study
• Already receiving the study drug
• Renal failure (eGRF < 30 mL/min) or dialysis/continuous veno-venous hemofiltration

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Kari AO Tikkinen, MD PhD; +358406510530; kari.tikkinen@helsinki.fi

Contact: Saana Horstia, RN; saana.horstia@hus.fi

• Listed Location Countries: Finland

Administrative Information

• NCT Number: NCT04978259
• Other Study ID Numbers: SOL21
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Kari Tikkinen, Clinical Urology and Epidemiology Working Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Clinical Urology and Epidemiology Working Group
• Original Study Sponsor: Same as current

Collaborators

• University of Helsinki
• World Health Organization
• Helsinki University Central Hospital
• Hyvinkää Hospital
• Kanta-Häme Central Hospital
• Kuopio University Hospital
• Oulu University Hospital
• Porvoo Hospital
• Seinajoki Central Hospital
• Mikkeli Central Hospital
• Tampere University Hospital

Investigators

• Study Director: Kari AO Tikkinen, MD PhD; University of Helsinki
• Principal Investigator: Olli Nevalainen, MD PhD; University of Helsinki

• PRS Account: Clinical Urology and Epidemiology Working Group
• Verification Date: June 2022