Long COVID
Conditions
Brief summary
Long COVID, also referred to as post-acute sequela of COVID-19 (PASC), is present in a substantial number of individuals, and treatment for this is warranted. Two different hypothetical models of Long COVID suggest attenuated mitochondrial energy production and functional brain alterations associated with psychosocial load, respectively, to be key mechanisms in the underlying pathophysiology. Given the potential importance of metabolic disturbances, dietary supplement by Nicotinamide Riboside (NR, sales name Niagen®) may be beneficial. Given the potential importance of functional brain alterations, a tailored and personalized Mind-Body Reprocessing Therapy (MBRT) may be beneficial. The MBRT consists of 4 to 6 face-to-face therapist encounters in combination with digital resources. The primary objective is to determine whether NR 1000 mg twice daily and/or MBRT increase health-related quality of life in individuals with Long COVID compared with care as usual and/or placebo. The Medical Outcome Study 36-item short form (SF-36), general health subscore is the primary endpoint. Secondary endpoints are: Markers of inflammation (hsCRP) and cognitive function (trail making test), cost-effectiveness, and the patient-reported symptoms fatigue, dyspnoea, and global impression of change in symptoms, function and quality of life. Explorative objectives encompass intervention effects on additional cognitive function markers, biological markers (indices of inflammation and autonomic nervous activity), disability markers (work attendance) and patient symptoms, as well as the exploration of long-term effects, differential subgroup effects, intervention effect mediators and intervention effect predictors. The study is a randomized controlled trial featuring a 2 x 2 factorial design where MBRT is compared with usual care and NR is compared with placebo. The latter comparison is double blinded. Eligible participants are individuals (18-70 years) with confirmed Long COVID interferring negatively with daily activities. A total of 310 participants will be enrolled. After baseline assessment (T1), the participants will be randomized 1:1 for both treatment comparisons, resulting in four treatment groups: a) MBRT and NR; b) usual care and NR; c) MBRT and placebo; d) usual care and placebo. All treatment periods last for three months, followed by primary endpoint assessment (T2). Total follow-up time is 12 months (T3). A comprehensive investigational program at all time points includes clinical examination, functional testing (spirometry, autonomic cardiovascular control, neurocognitive functions), sampling of biological specimens (blood) and questionnaire charting (background/demographics, clinical symptoms, psychosocial factors, study events).
Interventions
DIETARY_SUPPLEMENTNicotinamide Riboside (NR)
4 capsules (a total of 1000 mg) 2 times daily for 84 days
BEHAVIORALMind-body reprocessing therapy (MBRT)
4-6 face-to-face meetings over 3-4 weeks, unlimited access to designated online resources.
BEHAVIORALCare as usual
A brief self-help leaflet on long COVID is distributed, otherwise care as usual by the general practitioner
DIETARY_SUPPLEMENTPlacebo
4 capsules (empty) 2 times daily for 84 days.
Sponsors
University Hospital, Akershus
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
For the NR vs placebo comparison, participants, care providers, investigators and outcome assessors are blinded. For the MBRT vs. usual care comparison, due to the nature of the intervention, only outcome assessors are blinded
Intervention model description
A 2 x 2 factorial randomized controlled trial, where Mind-Body Reprocessing Therapy (MBRT) is compared with care as usual and Nicotinamide Riboside (NR) is compared with placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Undergone acute COVID-19, confirmed EITHER by a positive PCR-test OR a positive self-test combined with confirmatory antibody-pattern in blood. * Persistent symptoms at least 6 months following acute COVID-19 without symptom-free interval. * Functional disability to an extent that impacts negatively on normal activities (such as work attendance, physical exercise, social activities, etc.) * Informed consent
Exclusion criteria
* Other chronic illnesses, demanding life situations or concomitant drug use/substance abuse that is considered a plausible cause of persistent symptoms and associated disability * Sustained organ damage (lung, heart, brain) following acute, serious Covid-19 * Pregnancy. * Bedridden * Insufficient command of Norwegian
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Health-related quality of life | Three months after inclusion (T2) | The Medical Outcome Study 36-item short form (SF-36), general health subscore (total range 0 - 100, where higher scores indicate better QoL) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Executive functioning | Three months after inclusion (T2) | The Trail Making test, part B, seconds. Longer time indicates poorer executive functioning |
| Fatigue | Three months after inclusion (T2) | Chalder Fatigue Questionnaire (CFQ), total sum score (total range is from 0 - 33; higher scores indicate more fatigue) |
| Inflammation | Three months after inclusion (T2) | Plasma levels of C-reactive protein, high-sensitive assay (hsCRP). Higher levels indicate more inflammation |
| Global impression of change | Three months after inclusion (T2) | Patient Global Impression of Change (PGIC) inventory. Total range is from 1 - 7; higher scores imply that the health status is considered worsened |
| Cost-effectiveness | Three months after inclusion (T2) | Incremental cost-effectiveness ratio, using the 36-item short form (SF-36) general health subscore to determine quality-adjusted life years. |
| Dyspnoea | Three months after inclusion (T2) | Medical Research Council dyspnoea scale. Total range is from 0 - 4, where higher scores indicate more dyspnoea |
Other
| Measure | Time frame | Description |
|---|---|---|
| Smell and taste abnormalities | Three months after inclusion (T2) | Averaged score across two singel questionnaire items each scored on a 5-point Likert scale where higher scores means more symptoms |
| Working memory | Three months after inclusion (T2) | The digit span test, total score. Higher scores means better working memory |
| Inflammation, additional information | Three months after inclusion (T2) | Plasma levels of Interleukin (IL)-6. Higher levels means more inflammation. |
| Subjective cognitive difficulties | Three months after inclusion (T2) | Average score across 4 single items adressing subjective cognitive complaints, each scored on a 1-5 Likert scale. Higher scores means more subjective cognitive difficulties. |
| Physical functioning | Three months after inclusion (T2) | The Medical Outcome Study 36-item short form (SF-36), physical functioning subscore (total range 0 - 100, where higher scores indicate better physical functioning) |
| Social functioning | Three months after inclusion (T2) | The Medical Outcome Study 36-item short form (SF-36), social functioning subscore (total range 0 - 100, where higher scores indicate better social functioning) |
| Anxiety | Three months after inclusion (T2) | Hospital Anxiety and Depression Symptoms (HADS), anxiety sub-score |
| Worrying tendencies | Three months after inclusion (T2) | Penn State Worry Questionnaire (PSWQ), total sum score (higher scores means more worrying) |
| Sympathetic predominance | Three months after inclusion (T2) | Heart rate variability (HRV) indices in the time and frequency domain using a 5-minute ECG recording obtained during supine rest |
| Post-exertional malaise (PEM) | Three months after inclusion (T2) | PEM items from the DePaul Symptom Questionnaire, total average score across five items |
| Subjective pain experiences | Three months after inclusion (T2) | Brief Pain Inventory (BPI), average score |
| Sleep difficulties | Three months after inclusion (T2) | Karolinska sleep questionnaire (KSQ), total sum score |
| Depression | Three months after inclusion (T2) | Hospital Anxiety and Depression Symptoms (HADS), depression sub-score |
Countries
Norway
Outcome results
None listed