Mental Intervention and Nicotinamide Riboside Supplementation in Long Covid

Study Overview
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Brief Summary
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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 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 psychosocial factors, 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 (digit span 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 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 treatments 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).

Official Title
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The Efficacy and Safety of a Mental Intervention Program vs. Usual Care and Nicotinamide Riboside (NR) vs. Placebo for Improving Health-related Quality of Life in Long Covid: A 2 x 2 Factorial Randomized Controlled Trial

Conditions
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Long COVID

Intervention / Treatment
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* Dietary Supplement: Nicotinamide Riboside (NR)
* Behavioral: Mind-body reprocessing therapy (MBRT)
* Behavioral: Care as usual
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: MBRT and NR<br>Psychological therapy and dietary supplement | Dietary Supplement: Nicotinamide Riboside (NR)<br>* 4 capsules (a total of 1000 mg) 2 times daily for 84 days<br>Behavioral: Mind-body reprocessing therapy (MBRT)<br>* 4-6 face-to-face meetings over 3-4 weeks, unlimited access to designated online resources.<br>|
| Other: MBRT and placebo<br>Psychological therapy and placebo dietary supplement | Behavioral: Mind-body reprocessing therapy (MBRT)<br>* 4-6 face-to-face meetings over 3-4 weeks, unlimited access to designated online resources.<br>Dietary Supplement: Placebo<br>* 4 capsules (empty) 2 times daily for 84 days.<br>|
| Other: Care as usual and NR<br>No psychological therapy (information only) and dietary supplement | Dietary Supplement: Nicotinamide Riboside (NR)<br>* 4 capsules (a total of 1000 mg) 2 times daily for 84 days<br>Behavioral: Care as usual<br>* A brief self-help leaflet on long COVID is distributed, otherwise care as usual by the general practitioner<br>|
| Other: Care as usual and placebo<br>No psychological therapy (information only) and placebo dietary supplement | Behavioral: Care as usual<br>* A brief self-help leaflet on long COVID is distributed, otherwise care as usual by the general practitioner<br>Dietary Supplement: Placebo<br>* 4 capsules (empty) 2 times daily for 84 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health-related quality of life | The Medical Outcome Study 36-item short form (SF-36), general health subscore (total range 0 - 100, where higher scores indicate better QoL) | Three months after inclusion (T2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammation | Plasma levels of C-reactive protein, high-sensitive assay (hsCRP). Higher levels indicate more inflammation | Three months after inclusion (T2) | 
| Working memory | The Digit Span Test, total score, adopted from the Wechsler Adult Intelligence Scale (WAIS), 4th edition (WAIS-IV). Total range is from 0 - 30; higher scores indicate better working memory | Three months after inclusion (T2) | 
| Fatigue | Chalder Fatigue Questionnaire (CFQ), total sum score (total range is from 0 - 33; higher scores indicate more fatigue) | Three months after inclusion (T2) | 
| Dyspnoea | Medical Research Council dyspnoea scale. Total range is from 1 - 5, where higher scores indicate more dyspnoea | Three months after inclusion (T2) | 
| Global impression of change | Patient Global Impression of Change (PGIC) inventory. Total range is from 1 - 7; higher scores imply that the health status is considered worsened | Three months after inclusion (T2) | 
| Cost-effectiveness | Incremental cost-effectiveness ratio, using the 36-item short form (SF-36) general health subscore to determine quality-adjusted life years. | Three months after inclusion (T2) |