Mental Intervention and Nicotinamide Riboside Supplementation in Long Covid (MINIRICO)

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Long COVID
• Intervention / Treatment: Dietary supplement: Nicotinamide Riboside (NR); Behavioral: Mind-body reprocessing therapy (MBRT); Dietary supplement: Placebo; Behavioral: Care as usual

• Study Type: Interventional
• Enrollment (Actual): 310
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Lørenskog, Norway, 1478
    • Akershus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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)
Fatigue	Chalder Fatigue Questionnaire (CFQ), total sum score (total range is from 0 - 33; higher scores indicate more fatigue)	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)
Executive functioning	The Trail Making test, part B, seconds. Longer time indicates poorer executive functioning	Three months after inclusion (T2)
Dyspnoea	Medical Research Council dyspnoea scale. Total range is from 0 - 4, where higher scores indicate more dyspnoea	Three months after inclusion (T2)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Worrying tendencies	Penn State Worry Questionnaire (PSWQ), total sum score (higher scores means more worrying)	Three months after inclusion (T2)
Sympathetic predominance	Heart rate variability (HRV) indices in the time and frequency domain using a 5-minute ECG recording obtained during supine rest	Three months after inclusion (T2)
Post-exertional malaise (PEM)	PEM items from the DePaul Symptom Questionnaire, total average score across five items	Three months after inclusion (T2)
Sleep difficulties	Karolinska sleep questionnaire (KSQ), total sum score	Three months after inclusion (T2)
Subjective cognitive difficulties	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.	Three months after inclusion (T2)
Subjective pain experiences	Brief Pain Inventory (BPI), average score	Three months after inclusion (T2)
Depression	Hospital Anxiety and Depression Symptoms (HADS), depression sub-score	Three months after inclusion (T2)
Smell and taste abnormalities	Averaged score across two singel questionnaire items each scored on a 5-point Likert scale where higher scores means more symptoms	Three months after inclusion (T2)
Working memory	The digit span test, total score. Higher scores means better working memory	Three months after inclusion (T2)
Inflammation, additional information	Plasma levels of Interleukin (IL)-6. Higher levels means more inflammation.	Three months after inclusion (T2)
Anxiety	Hospital Anxiety and Depression Symptoms (HADS), anxiety sub-score	Three months after inclusion (T2)
Physical functioning	The Medical Outcome Study 36-item short form (SF-36), physical functioning subscore (total range 0 - 100, where higher scores indicate better physical functioning)	Three months after inclusion (T2)
Social functioning	The Medical Outcome Study 36-item short form (SF-36), social functioning subscore (total range 0 - 100, where higher scores indicate better social functioning)	Three months after inclusion (T2)

Collaborators and Investigators

• Sponsor: University Hospital, Akershus
• Investigators: Study Chair: Torbjørn Omland, PhD, Akershus University Hospital/University of Oslo

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2023
• Primary Completion (Actual): September 23, 2024
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: January 25, 2023
• First Submitted That Met QC Criteria: January 25, 2023
• First Posted (Actual): January 27, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 3, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Post-Infectious Disorders; COVID-19; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Post-Acute COVID-19 Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Micronutrients; Vitamin B Complex; Vitamins; Vasodilator Agents; Hypolipidemic Agents; Lipid Regulating Agents; Niacin; Niacinamide; Nicotinic Acids
• Other Study ID Numbers: 983971636

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No