Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04851561 |
| Other study ID # |
RMC-0834-20 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 2, 2021 |
| Est. completion date |
August 24, 2021 |
Study information
| Verified date |
April 2021 |
| Source |
Rabin Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Background: COVID-19 is consistently spreading throughout the world, and the number of
recovered patients is steadily increasing. Accordingly, a significant number of individuals
will develop persisting post-COVID symptoms, while many of them will report on lasting
fatigue. The main objective of the current study is to assess risk factors for the
development of post-COVID-19 fatigue symptoms. As a secondary aim, the current study is
intended to identify pathophysiology and explanatory mechanisms for the post-COVID-19
fatigue.
Study design and population: a nested case-control study will be conducted at Rabin Medical
Center (RMC), Beilinson Hospital. RMC runs a post-COVID-19 clinic for adult (age ≥18 years)
recovered individuals (diagnosed using a polymerase chain reaction test from a nasopharyngeal
sample), who are invited for a comprehensive medical evaluation. During a visit, all
individuals undergo pulmonary function testing and an evaluation by an infectious diseases
physician, a pulmonologist, and a social worker. The cohort of recovered COVID-19 individuals
evaluated at RMC will serve as the population from which the current study participants will
be consecutively sampled. The cases would be defined as such if report on lasting fatigue
symptoms which appeared following COVID-19, while at least two months have elapsed since
COVID-19 diagnosis and the lasting fatigue symptoms are present for at least six weeks. The
controls would be defined as those that did not report on fatigue symptoms at any time point
since one month following their diagnosis with COVID-19.
Evaluation protocol of cases and controls: All participating individuals (cases and controls)
will be assessed following the study protocol. The assessment will be conducted as follows:
First assessment meeting (approximately one hour long) in which the participant will undergo
physical examination and blood tests, fill the study questionnaires [demographic, clinical
and post-COVID fatigue questionnaire; sleep assessment questionnaires (Epworth sleepiness
score [ESS], Pittsburg sleep quality index [PSQI], Insomnia severity index (ISI)]) and
depression severity questionnaire (the patient health questionnaire-9 [PHQ-9]), and conduct
cognitive fatigue task.
Second assessment meeting: (approximately one hour long) in which the participants will
undergo a cardiopulmonary stress test (CPET).
Data collection: The main dependent variable will be the presence of continuing fatigue
symptoms. The independent variables included demographic and clinical characteristics. The
demographic variables will include: age at diagnosis, sex, marital status and number of
children, occupational status (employed, unemployed, or retired), education (number of years
at school and higher education), and occupation. The clinical variables will include: smoking
status, alcohol and cannabis consumption, basic physical function (independent, limited in
certain activities, dependent in activities of daily living, or bedridden), background
illnesses, and pharmacotherapy. The acute COVID-19 history will be also collected: disease
severity according to the WHO criteria, symptoms (sore throat, nasal congestion, headache
anosmia/disguesia, cough, shortness of breath, chest pain, gastrointestinal symptoms, and
myalgia), need for hospitalization, hospital complications (veno-thromboembolism,
super-imposed bacterial infections), for individuals who were not hospitalized - the site of
isolation (home, hotel or another isolation facility) will be collected, time from onset to
symptoms resolution, pharmacotherapy directed at COVID-19, and information of other household
or family members who were also diagnosed.
Statistical methods: Demographic and clinical variables of the patients with fatigue symptoms
(cases) and control group (free from fatigue symptoms) will be compared using bivariate and
multivariable conditional logistic regression models. Independent variables will be selected
to be included in the multivariable model based on the bivariate analysis. Odds ratios and
95% confidence intervals will be obtained from the conditional logistic regression models.
P<0.05 will be considered statistically significant.
Sample size calculation: Disease severity may serve as a potential risk factor for the
development of lasting fatigue symptoms. A preliminary analysis revealed that in our cohort
of recovered COVID-19 patients, 20% were hospitalized due to their disease's severity. We
will therefore assume that the proportions of individuals required hospitalization during the
acute phase were 30% and 10% of the cases and controls, respectively. It is also likely that
approximately two thirds of our sample would report on persisting fatigue. Under these
assumptions, a sample size of 153 individuals (102 in the cases group and 51 in the control
group) will yield a statistical power of 80% at a significance level of 5% for detecting a
difference of 0.2 between two proportions.
Description:
The evaluation of both cases and controls will include the following:
- Physical examination: a comprehensive physical examination, including neurological
assessment of motor function.
- Blood tests: complete blood count, C-reactive protein, erythrocyte sedimentation rate,
thyroid functions (TSH, fT3, fT4), kidney and liver functions, creatine phosphokinase,
serum electrolytes, Epstein-Barr virus and cytomegalovirus serology testing, ferritin,
and serum vitamin B12 and folate levels.
- Sleep assessment: in order to estimate the quality and characteristics of sleep, the
participating individuals will independently fill the following sleep assessment
questionnaires:
- Epworth sleepiness score (ESS) - to generally evaluate subjective sleepiness (was
validated in Hebrew).
- Pittsburg sleep quality index (PSQI) - to evaluate the quality of sleep (was
validated in Hebrew).
- Insomnia severity index (ISI) - to evaluate insomnia (a Hebrew version exists, but
the questionnaire is yet to be validated).
- Depression severity questionnaire: in order to screen for depression and to estimate the
degree of depression severity, the participating individuals will independently fill the
patient health questionnaire-9 (PHQ-9).
- Fatigue classification tool
For chronic fatigue syndrome, the Centers for Disease Control and Prevention (CDC) adopted
the clinical case definition suggested by the Institute of Medicine (IOM), and consolidated
criteria. We adopted the portion on fatigue from the CDC criteria for chronic fatigue
syndrome, and modified it to suit for the time frame and relations with COVID-19:
Patient has a substantial reduction or impairment in the ability to engage in pre-illness
levels of occupational, educational, social, or personal activities that persists for >6
weeks and is accompanied by fatigue, which is often profound, is of new onset (appeared after
the diagnosis of COVID-19), is not the result of ongoing excessive exertion, and is not
substantially alleviated by rest. These symptoms are present at least half of the day time,
to at least a moderately severe degree.
Each participant will independently fill a designated form in which the aforementioned
criteria will be mentioned, followed by to statement from which the participant will circle
the one relevant for him:
- The criteria above accurately describe my current situation.
- The criteria above do not accurately reflect my current situation.
- Assessment of exercise physiology: All participants will undergo a cardiopulmonary
stress test (CPET), under the guidance of sports and exercise physicians and
nursing staff. Electrocardiogram, spirometry, blood pressure and gas exchange
measuring will be assessed at rest. The participants will then undergo CPET
according to a modified Astrand treadmill test protocol. The test will be
terminated at maximal exercise or upon the appearance of limiting symptoms .
Continuous electrocardiogram and repeated blood pressure measuring will be
conducted at the recovery phase. Post-exercise spirometry will also be assessed.
- Assessment of cognitive fatigue: in order to assess cognitive fatigue, all
participants will undergo the visual vigilance test. This test, that was designed
to be a measure of sustained attention, was previously implemented in individuals
with multiple sclerosis. This test will be conducted in a designated room in which
the participants will seat in front of a computer, and will independently conduct
the task after being instructed by the primary investigator or one of the
sub-investigators. During the task, the different alphabetical letters will be
screened at a rate of 500 milliseconds per each. The tested individual will be
instructed to press the space button whenever two specific letters (i.e. the target
letters) are presented. A total of 600 letters will be screened, of which 120 will
be the target letters. The test is to be repeated 3 times, 5 minutes for each run.
The percentage of correct presses, the number of errors and the mean reaction time
will be evaluated for each time period.
