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
Phase: PHASE2
Conditions: Long COVID
Sponsor: University Hospital, Akershus

Protocol: MINIRICO trial
 
© 2015-2021 TransCelerate BioPharma 
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Title Page 
 
Protocol Title:  
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 
 
Amendment Number: #2 
 
Brief Title: Mental Intervention and NIcotinamide RIboside supplementation in long COvid 
 
Acronym: MINIRICO 
 
Study Phase: 2B  
 
Sponsor Name: Akershus University Hospital, Sykehusveien 25, P.O.Box 1000, N-1478 Lørenskog, 
Norway 
 
REK approval Date: 18.11.2022, ref. nr. 533539 
Independent Monitor Committee, Contact Information: Ass. Prof. Melanie Rae Simpson, NTNU, 
Melanie.simpson@ntnu.no.  
 
Amendment #2, 2025/01/23: Summary of amendments  
In January 2025, prior to analyses of main results from the trial, the following protocol amendments 
have been implemented:  
• Insertion of correct ClinicalTrials ID.  
• Slight adjustment of the study rationale due to recent empirical and theoretical development in 
neurobiological models of symptom persistence in general (Chapter 1 and 2).  
• Adjustments of secondary and exploratory endpoints (paragraph 3,1, Table 2) bringing them up-to-
date with recent scientific literature on the post-COVID-19 condition. In particular, executive 
functioning is seen as a more relevant neurocognitive marker than working memory in the 
population under study; the Trail Making Test, part B, is therefore included as a secondary outcome 
measure, substituting Digit Span Total Score which is now included as an exploratory outcome 
measure. Furthermore, the number of exploratory endpoints is moderately expanded to encompass 
more facets of potential intervention effects (on inflammation, symptoms, and physical/social 
functioning). The explorative endpoint related to attention bias has been removed as we were 
unable to establish the necessary experimental set-up; the description on functional testing 
procedures (paragraph 8.1.2) is revised accordingly.  
• Addition of other objectives related to important RCT design issues, such as compliance, therapist 
fidelity, dose-response associations, and the effect of prior confidence in the interventions under 
study (paragraph 3.2, Table 3).  

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• Rephrasing of the primary estimand paragraph to avoid ambiguities and harmonize with similar 
statements in the Statistical Analysis Plan (paragraph 3.3). 
• Slight adjustments of safety monitoring routines, specifying that questionnaires on side effects were 
administered twice during the intervention period (paragraph 4.1).  
• Minor adjustment of compliance assessment, specifying that the number of self-directed activities 
in the MBRT intervention where charted at two time points, and that therapist fidelity is assessed 
from audio recordings of therapy sessions only (paragraph 6.5).  
• Addition of a qualitative sub-study with the aim of exploring participants’ experiences with the 
MBRT intervention (paragraph 8.13). Details of this substudy is outlined in a separate protocol.  
• Adding some information to the eligibility screening procedure (paragraph 8.2).  
• Specifying more details pertaining to the definition of the per-protocol analysis set (paragraph 9.2). 
• Providing a detailed description of the committee structure of MINIRICO (paragraph 10.1.6).  
• Updating the specific procedures for SAE reports (paragraph 10.2.4).  
All amendments were performed prior to database lock and any statistical analyses. They are visualized 
with “tracked changes” throughout the document. The final version of the protocol is endorsed by the 
steering committee of MINIRICO and published on the designated ClinicalTrials website.  

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Table of Contents 
Title Page ....................................................................................................................................... 1 
List of Abbreviations ................................................................... Feil! Bokmerke er ikke definert. 
1. 
Protocol Summary ......................................................................................................... 6 
1.1. 
Synopsis ........................................................................................................................... 6 
1.2. 
Schema ............................................................................................................................. 7 
1.3. 
Schedule of Activities (SoA) ........................................................................................... 9 
2. 
Introduction .................................................................................................................. 11 
2.1. 
Study Rationale .............................................................................................................. 11 
2.2. 
Background .................................................................................................................... 11 
2.3. 
Benefit/Risk Assessment ............................................................................................... 13 
2.3.1. 
Risk Assessment ............................................................................................................ 13 
2.3.2. 
Benefit Assessment ........................................................................................................ 14 
2.3.3. 
Overall Benefit Risk Conclusion ................................................................................... 14 
3. 
Objectives, Endpoints, and Estimands....................................................................... 15 
4. 
Study Design ................................................................................................................. 19 
4.1. 
Overall Design ............................................................................................................... 19 
4.2. 
Scientific Rationale for Study Design............................................................................ 20 
4.2.1. 
Patient Input into Design................................................................................................ 20 
4.3. 
Justification for Dose ..................................................................................................... 21 
4.4. 
End-of-Study Definition ................................................................................................ 21 
5. 
Study Population .......................................................................................................... 22 
5.1. 
Inclusion Criteria ........................................................................................................... 22 
5.2. 
Exclusion Criteria .......................................................................................................... 22 
5.3. 
Lifestyle Considerations ................................................................................................ 23 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................... 23 
5.3.2. 
Caffeine, Alcohol, and Tobacco .................................................................................... 23 
5.3.3. 
Activity........................................................................................................................... 23 
5.3.4. 
Other Restrictions .......................................................................................................... 23 
5.4. 
Screen Failures ............................................................................................................... 23 
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention ..................... 23 
6. 
Study Intervention(s) and Concomitant Therapy ..................................................... 24 
6.1. 
Study Intervention(s) Administered ............................................................................... 24 
6.1.1. 
Medical Devices ............................................................................................................. 25 
6.2. 
Preparation, Handling, Storage, and Accountability ..................................................... 25 
6.3. 
Assignment to Study Intervention ................................................................................. 25 
6.4. 
Blinding.......................................................................................................................... 25 
6.5. 
Study Intervention Compliance ..................................................................................... 25 
6.6. 
Dose Modification ......................................................................................................... 26 
6.6.1. 
Retreatment Criteria ....................................................................................................... 26 
6.7. 
Continued Access to Study Intervention after the End of the Study ............................. 26 
6.8. 
Treatment of Overdose ............................................... Feil! Bokmerke er ikke definert. 
6.9. 
Prior and Concomitant Therapy ..................................................................................... 26 

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6.9.1. 
Rescue Medicine ............................................................................................................ 27 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ....................................................................................... 28 
7.1. 
Discontinuation of Study Intervention ........................................................................... 28 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................................................. 28 
7.1.2. 
QTc Stopping Criteria .................................................................................................... 28 
7.1.3. 
Temporary Discontinuation ........................................................................................... 28 
7.1.4. 
Rechallenge .................................................................................................................... 28 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................................... 28 
7.3. 
Lost to Follow up ........................................................................................................... 29 
8. 
Study Assessments and Procedures ............................................................................ 30 
8.1. 
Administrative and General/Baseline Procedures ......................................................... 30 
8.2. 
Efficacy Assessments..................................................................................................... 34 
8.3. 
Safety Assessments ........................................................................................................ 34 
8.3.1. 
Physical Examinations ................................................................................................... 35 
8.3.2. 
Vital Signs ...................................................................................................................... 35 
8.3.3. 
Electrocardiograms ........................................................................................................ 35 
8.3.4. 
Clinical Safety Laboratory Tests .................................................................................... 35 
8.3.5. 
Pregnancy Testing .......................................................................................................... 35 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................... 36 
8.4. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and Other 
Safety Reporting ............................................................................................................ 36 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................... 36 
8.4.2. 
Method of Detecting AEs and SAEs .............................................................................. 36 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................... 36 
8.4.4. 
Regulatory Reporting Requirements for SAEs .............................................................. 37 
8.4.5. 
Pregnancy ....................................................................................................................... 37 
8.4.6. 
Cardiovascular and Death Events .................................................................................. 37 
8.4.7. 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs ............................................................................................ 37 
8.4.8. 
Adverse Events of Special Interest ................................................................................ 37 
8.4.9. 
Medical Device Deficiencies ......................................................................................... 37 
8.5. 
Pharmacokinetics ........................................................................................................... 38 
8.6. 
Pharmacodynamics ........................................................................................................ 38 
8.7. 
Genetics.......................................................................................................................... 38 
8.8. 
Biomarkers ..................................................................................................................... 38 
8.9. 
Immunogenicity Assessments ........................................................................................ 39 
8.10. 
Health Economics .......................................................................................................... 39 
9. 
Statistical Considerations ............................................................................................ 40 
9.1. 
Statistical Hypotheses .................................................................................................... 40 
9.1.1. 
Multiplicity Adjustment ................................................................................................. 40 
9.2. 
Analysis Sets .................................................................................................................. 40 
9.3. 
Statistical Analyses ........................................................................................................ 41 
9.3.1. 
General Considerations .................................................................................................. 41 
9.3.2. 
Primary [Endpoint(s)/Estimand(s)] Analysis ................................................................. 41 
9.3.3. 
Secondary [Endpoint(s)/Estimand(s)] Analysis ............................................................. 42 

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9.3.4. 
[Tertiary/Exploratory/Other] [Endpoint(s)/Estimand(s)] Analysis ................................ 42 
9.3.5. 
[Other] Safety Analyses ................................................................................................. 42 
9.3.6. 
Other Analyses ............................................................................................................... 42 
9.4. 
Interim Analysis ............................................................................................................. 42 
9.5. 
Sample Size Determination............................................................................................ 42 
10. 
Supporting Documentation and Operational Considerations ................................. 44 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........................ 44 
10.1.1. Regulatory and Ethical Considerations .......................................................................... 44 
10.1.2. Financial Disclosure ....................................................................................................... 44 
10.1.3. Informed Consent Process ............................................................................................. 44 
10.1.4. Recruitment strategy ...................................................................................................... 44 
10.1.5. Data Protection ............................................................................................................... 45 
10.1.6. Committees Structure ..................................................................................................... 45 
10.1.7. Data Quality Assurance ................................................................................................. 45 
10.1.8. Source Documents. ........................................................................................................ 46 
10.1.9. Study and Site Start and Closure.................................................................................... 46 
10.1.10. Publication Policy .......................................................................................................... 46 
10.2. 
Appendix 2: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................... 47 
10.2.1. Definition of AE............................................................................................................. 47 
10.2.2. Definition of SAE .......................................................................................................... 48 
10.2.3. Recording and Follow-Up of AE and/or SAE ............................................................... 49 
10.2.4. Reporting of SAEs ......................................................................................................... 50 
10.3. 
Appendix 3: Protocol Amendment History ................................................................... 51 
11. 
References ..................................................................................................................... 52 
 

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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: 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 
 
Brief Title: Mental Intervention and NIcotinamide RIboside supplementation in long COvid 
(MINIRICO)  
 
ClinicalTrials ID: NCT05703074 
 
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 partly 
caused by 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 available through the DIGNIO® interface.  
 
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 objectives are to determine intervention effects on six secondary endpoints: 
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 autonomic nervous activity and inflammation), 
disability markers (work attendance, quality of life) 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 (Figure 1). The latter comparison is double blinded. 
Eligible participants are individuals (18-70 years) with confirmed Long COVID interfering negatively 
with daily activities (such as work, socially, normal leisure activities, etc.). Participants will be 
recruited directly through self-referrals and referrals from general practitioners and hospital services, as 
well as from previous COVID-19 studies at our institution. 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. The intervention period last for three months, followed by primary endpoint 
assessment (T2). Total follow-up time is 12 months (T3). A comprehensive investigational program at 

Protocol: MINIRICO trial
 
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Figure 1.  
Study design  
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).  
 
1.2. 
Schema 
 
  

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Protocol MINIRICO trial  
 
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1.3. 
Schedule of Activities (SoA) 
 
Table 1. Schedule of Activities 
Procedure 
 
 
 
 
 
Screening  
(up to 30 
days before 
Day 1) 
Intervention Period (weeks) 
Early 
discon-
tinuation 
Follow-
up (40 
weeks 
after last 
end of 
interven
tion) 
1 
2 
3 
4 
5 
6 
7 
8 
9-
11 
12 
Basic demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
assessment 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination including urine 
analysis (dipstick analyses and 
pregnancy tests for woman 18-50 ys.) 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Sampling of biological specimens 
(blood) 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Questionnaire 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Functional assessments (spirometry, 
autonomic cardiovascular control, 
neurocognitive functions) 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Study intervention #1 – MBRT vs. 
care as usual. 
 
=============================→ 
 
 

 
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Table 1. Schedule of Activities 
Procedure 
 
 
 
 
 
Screening  
(up to 30 
days before 
Day 1) 
Intervention Period (weeks) 
Early 
discon-
tinuation 
Follow-
up (40 
weeks 
after last 
end of 
interven
tion) 
1 
2 
3 
4 
5 
6 
7 
8 
9-
11 
12 
Study intervention #2 – NR capsules 
1000 mg x 2 daily vs placebo capsules 
x 2 daily 
 
=============================→ 
 
 
AE review  
 
=============================→ 
X 
X 
Unsolicited AEs 
 
=============================→ 
X 
X 
SAE review 
 
=============================→ 
X 
X 
Concomitant medication review 
 
=============================→ 
X 
X 
 
 

 
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2. 
Introduction 
2.1. 
Study Rationale 
Recent studies show that long-term symptoms following COVID-19, commonly referred to as Long 
COVID, is present in a substantial number of individuals (Crook 2021; Soriano 2022) and treatment for 
this is warranted. 
 
The underlying pathophysiology of Long COVID remains to be resolved. As metabolic abnormalities 
characterized by attenuated mitochondrial function and increased anaerobic energy production appears 
to be features of other post-infective fatigue states (Sweetman 2020; Navieaux 2016; Lien 2019), it has 
been suggested that similar mechanisms may underlie Long COVID. However, psychosocial risk 
factors appear to be better predictors of Long COVID than biological and disease-specific factors, as 
recently documented in observational cohort studies across different countries (Selvakumar 2022; Berg 
2022; Stephenson 2022). Psychosocial load may be main contributors to functional brain alterations 
which in turn may explain symptom persistence (Van den Bergh 2017).  
 
Given the potential importance of metabolic disturbances, dietary supplement by Nicotinamide riboside 
(commonly referred to as NR) - a vitamin precursor converted to nicotinamide adenine dinucleotide 
(NAD+) in vivo that boosts mitochondrial energy production - may hold promise for improving 
symptoms and increasing functioning, and thereby increase health-related quality of life (Trammell 
2016).  
 
Given the potential importance of functional brain alterations related to psychosocial load, cognitive 
interventions have shown promise as treatment for persistent symptoms following infection, as well as 
for other illnesses with similar symptomatology as Long COVID (Keijmel 2017). A tailored and 
personalized cognitive approach that combines therapist contact with digital content and follow-up, 
may therefore have potential for improving symptoms and increasing functioning, and thereby increase 
health-related quality of life.  
 
2.2. 
Background 
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2). The clinical presentation of acute infection varies from asymptomatic infection over 
mild upper respiratory tract illness to severe viral pneumonia causing Acute Respiratory Distress 
Syndrome (ARDS) and respiratory failure. Old age and chronic cardiovascular morbidity are important 
risk factors for severe outcome (Zhou 2020). Recent studies show that long term symptoms following 
COVID-19, commonly referred to as Long COVID, is present in a substantial number of individuals 
(Crook 2021; Soriano 2022), and treatment for this is warranted.  
 
Evidence suggests that most Long COVID cases fit within the label of Persistent Post-Infectious 
Symptoms (PPIS), encompassing chronic fatigue, pain and other symptoms, but with scarce findings on 
clinical examination (Sandler 2021). PPIS is a common sequel after several acute infections with a 
diverse array of pathogens, such as infectious mononucleosis (IM) caused by Epstein-Barr virus, Q-
fever caused by the bacterium Coxiella burnetii, and gastroenteritis caused by the parasite Giardia 

 
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Figure 2.  
COVID-19 
weekly 
inci-
dence and an estimate of 
Long COVID prevalence 
(based on 10 % and 5 % 
case rate, respectively, 6 
and 12 months after the 
acute infection). 
lamblia. (Hickie 2006, Hanevik 2014). Across multiple prospective cohort studies, almost one half of 
subjects report PPIS six months after the infectious event, and 10-15 % satisfy diagnostic criteria for 
the chronic fatigue syndrome (Hanevik 2014; Buchwald 2000; Hickie 2006; Pedersen 2019). Although 
late recovery may occur chronic disability is common. Given the total number of COVID-19 cases 
globally, Long COVID may be considered as an epidemic in its own right (Figure 2).   
 
Long COVID is primarily defined from patients’ subjective experience of symptoms (Soriano 2022). 
These symptoms may vary considerably between individuals; while fatigue, dysnoea and “brain fog” 
are seen as hallmark  of the conditions, complaints such as post-exertional malaise (PEM), sleep 
difficulties, pain, altered smell/taste and depression/anxiety may be features of Long COVID, either 
alone or in combination (Soriano 2022). As is the case with other PPIS, no biomarkers nor other factors 
that can be objectively measured are consistently associated with Long COVID. Hence, patient 
reported outcome measures (PROMs) are seen as the most valid measures to assess treatment effects. 
Also, a thorough diagnostic assessment at inclusion is required to rule out alternative conditions that 
may be associated with persistent symptoms, as Long COVID is considered a diagnosis of exclusion 
(Selvakumar 2022). 
 
The pathophysiology of Long COVID as well as PPIS in general remains to be resolved. Largely 
speaking, two alternative hypothetical models have been proposed: One model assumes autoimmunity 
to be the underlying mechanisms (Blomberg 2018), supported by reports of low-grade systemic 
inflammation (Montoya 2017; Nguyen 2017) possibly linked to mitochondrial dysfunction and 
increased anaerobic energy production (Ajaz 2021; Magnani 2020; Sweetman 2020; Navieaux 2016; 
Lien 2019). In support of this model, a modest increase of plasma inflammatory markers has been 
reported across several Long COVID studies (Sommen 2022; Mehandru 2022; Peluso 2021; Vono 
2021). 
 
Another model considers functional brain alterations to be the central pathophysiological element 
(Henningsen 2018; Wyller 2009; Van den Bergh 2017), supported by functional brain imaging studies 
(Almutari 2020; Wortinger 2016 & 2017) and clinical trial outcomes (Kejmel 2017). The latter 
alternative is assumed to be driven by neurocognitive aberrations such as cognitive fusion and attention 
bias, which in turn may be linked to personality traits, worrying tendencies and loneliness (Wyller 
2009). A recent observational cohort study conducted by our research group provides some support for 
this model, finding that risk of Long COVID was related to baseline personality traits and loneliness, 
but not to biological markers (Selvakumar 2022). In addition, this model hypothesizes that the 
functional brain alterations result in a sympathetic predominance of autonomic nervous system activity 
which in turn may impact on immunological functions, as has indeed been reported in several previous 
PPIS studies (Jason 2021; Katz 2019; Kristensen 2019).  
 

 
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Nicotinamide riboside (NR,sales name Niagen®), a vitamin precursor converted to nicotinamide 
adenine dinucleotide (NAD+) in vivo (Airhart 2017), acts as a co-factor in several vital metabolic 
pathways, including aerobic energy production in the mitochondria. NR seems to reduce neurological 
inflammation and is currently being tested in disorders such as Amyotrophic Lateral Sclerosis (ALS), 
Parkinson’s disease and neurological complications of diabetes mellitus. (Obrador 2021; Lee 2019; 
Maynard 2020; Chandrasekaran 2019; Chandrasekaran 2020; Mehmel 2020). Recent data suggest that 
NR supplementation increased brain NAD+ levels that was associated with altered brain metabolism 
(Brakedal et al 2022). There is also preliminary evidence for a beneficial effect in acute COVID-19, 
possibly due to a dampening effect on the hyperinflammatory state associated with severe acute 
infection (Mehmel 2020). Assuming that Long COVID and other chronic fatigue conditions are caused 
by mitochondrial dysfunction and subsequent inflammation, NR dietary supplement may hold promise 
for a beneficial effect. 
 
A recent meta-analysis concluded that the mental intervention method Acceptance and Commitment 
Therapy (ACT) is among the most promising interventions when it comes to persisting symptoms, 
somatic and/or psychological, with superior results compared to active control conditions (Gloster et al 
2020). In terms of fatigue, Norwegian studies conducted by members of the research team show effects 
of ACT on persistent fatigue (Jacobsen et al 2017 and 2020). Related mental interventions, such as 
Cognitive Behavioural Therapy (CBT), has previously been demonstrated to be effective in PPIS 
(Kejmel 2017) as well as in Long COVID (Kuut et al 2021, 2023). Also, CBT delivered via the internet 
has been shown to be effective against chronic fatigue states (Janse 2018). Assuming that Long COVID 
is mainly caused by functional brain aberrations, a tailored and personalized cognitive approach (Mind-
Body Reprocessing Therapy, MBRT) using elements from ACT as well as related techniques, and 
combining therapist contact with digital content and follow-up, may have potential. 
 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably expected 
adverse events (AEs) of MBRT and NR may be found in the participant information leaflet. A Data 
Monitoring Committee will be established and given an independent responsibility for overseeing 
adverse effects related to the intervention, cf. paragraphs 9 and 10. 
 
2.3.1. 
Risk Assessment 
Investigational Intervention 
• Psychological interventions have been shown safe to use as treatment in other PPIS as well as in 
persistent symptom conditions in general, with no serious adverse events (Kejmel 2017; White 
2011; Nijhof 2012; Janse 2018; Kuut et al 2023). The internet-based format of part of the MBRT 
reduces burden on the participants and secures therapy delivery. 
• NR is a dietary supplement, where dosage of 1000 mg x 2 daily has been shown safe with no 
adverse events reported (Mehmel 2020; Airhart 2017). Furthermore, NR was awarded status as 
“generally recognized as safe” by the Federal Drug Administration (FDA) in the USA in 2016 
(GRAS No. 635). In a recent study of toxicity, daily doses up to 1200 mg/kg were well tolerated in 
rats (Marinescu 2020). Regarding embryo-fetal developmental toxicity, a rat study found a no 
observed adverse effect level (NOAEL) of 325 mg/kg, corresponding to a daily intake of more than 
22,000 mg in an adult of 70 kg (EFSA Panel on Nutrition, 2019).    

 
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Study Procedures 
• Blood samples collected through venous puncture is the most intrusive procedure in this study. The 
risk of this procedure is low and well accepted in general. 
• As there is no known medical treatment for persistent symptoms following COVID-19, there is no 
known risk for giving placebo hence not giving medical treatment to half of the participants. 
 
2.3.2. 
Benefit Assessment 
The participants in the study may benefit from a thorough medical examination that may identify other 
health issues. Also, the subgroups of participants allocated to the active treatment arms may benefit 
from potential effective therapies against Long COVID. In general, for patients with Long COVID and 
for the society, there are huge benefits in identifying potential therapeutic options against this 
condition, givens its high prevalence and disabling consequences.  
 
2.3.3. 
Overall Benefit Risk Conclusion 
Taking into account the measures taken to minimize risk to participants participating in this study, the 
potential risks identified in association with the MBRT and NR interventions are justified by the 
anticipated benefits for participants, Long COVID patients in general, and the society at large. 

 
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3. 
Objectives, Endpoints, and Estimands 
 
 
3.1. Main intervention effects 
 
A total of 20 endpoints are directly related to intervention effects, as outlined in Table 2. The study has 
one primary endpoint (A1), six secondary endpoints (B1-6), and 13 exploratory endpoints (C1-13), all 
evaluated at T2.   
 
Table 2. Assessment of intervention effects 
 
Objectives 
Endpoints 
A 
Primary  
A1 
To determine whether MBRT/NR increases health-related quality 
of life in individuals with Long COVID compared with care as 
usual/placebo. 
The Medical Outcome Study 36-item 
short form (SF-36), general health 
subscore (Jacobsen 2018) 
B 
Secondary 
B1 
To determine whether MBRT/NR reduces markers of 
inflammation in individuals with Long COVID compared with care 
as usual/placebo 
Plasma levels of C-reactive protein, high-
sensitive assay (hsCRP) (Pedersen 
2019) 
B2 
To determine whether MBRT/NR increases executive 
functioning in individuals with Long COVID compared with care 
as usual/placebo.  
The Trail Making Test, part B, of 
neurocognitive functioning (Reitan 1958)  
B3 
To determine whether MBRT/NR reduces fatigue in individuals 
with Long COVID compared with care as usual/placebo 
Chalder Fatigue Questionnaire (CFQ), 
total sum score (Chalder 1993) 
B4 
To determine whether MBRT/NR reduces dyspnoea in individuals 
with Long COVID compared with care as usual/placebo 
Medical Research Council dyspnoea 
scale (Bestall 1999) 
B5 
To determine whether MBRT/NR impact on patients’ global 
impression of change in symptoms, functions and quality of 
life in individuals with Long COVID compared with care as 
usual/placebo 
Patient Global Impression of Change 
(PGIC) inventory (Hurst 2004) 
B6 
To determine whether MBRT/NR increases cost-effectiveness in 
individuals with Long COVID compared with care as usual/placebo 
Incremental cost-effectiveness ratio, 
using the 36-item short form (SF-36) 
general health subscore to determine 
quality-adjusted life years. 
C 
Exploratory 
C1 
To determine whether MBRT/NR reduces markers of 
inflammation (other than hsCRP) in individuals with Long 
COVID compared with care as usual/placebo  
Plasma levels of interleukin (IL)-6. 
C2 
To determine whether MBRT/NR increases working memory in 
individuals with Long COVID compared with care as usual/placebo 
The Digit Span Test, total score (Grizzle 
2011) 
 
C3 
To determine whether MBRT/NR reduces worrying tendencies in 
individuals with Long COVID compared with care as usual/placebo 
Penn State Worry Questionnaire 
(PSWQ), total sum score (Pallesen 
2006) 

 
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C4 
To determine whether MBRT/NR reduces sympathetic 
predominance of autonomic cardiovascular control in 
individuals with Long COVID compared with care as usual/placebo 
Heart rate variability (HRV) indices in the 
time and frequency domain using a 5-
minute ECG recording obtained during 
supine rest (Task Force 1996) 
C5 
To determine whether MBRT/NR reduces post-exertional 
malaise (PEM) in individuals with Long COVID compared with 
care as usual/placebo. 
PEM items from the DePaul Symptom 
Questionnaire, total average score 
across five items (Bedree 2019) 
C6 
To determine whether MBRT/NR reduces pain in individuals with 
Long COVID compared with care as usual/placebo 
Brief Pain Inventory (BPI), average score 
(Klepstad 2002) 
 
C7 
To determine whether MBRT/NR reduces sleep difficulties in 
individuals with Long COVID compared with care as usual/placebo 
Karolinska sleep questionnaire (KSQ), 
total sum score (Akerstedt 20089) 
C8 
To determine whether MBRT/NR reduces subjective cognitive 
difficulties in individuals with Long COVID compared with care as 
usual/placebo 
Cognitive items from Chronic Fatigue 
Symptom inventory, average score 
across four items (Selvakumar 2022) 
C9 
To determine whether MBRT/NR reduces depression in 
individuals with Long COVID compared with care as usual/placebo 
Hospital Anxiety and Depression 
Symptoms (HADS), Depression 
subscore (Zigmond 1983) 
C10 
To determine whether MBRT/NR reduces anxiety in individuals 
with Long COVID compared with care as usual/placebo 
Hospital Anxiety and Depression 
Symptoms (HADS), Anxiety subscore 
(Zigmond 1983) 
C11 
To determine whether MBRT/NR reduces altered smell and taste 
in individuals with Long COVID compared with care as 
usual/placebo 
Upper airways symptoms, two single 
items (Wagner 2005) 
C12 
To determine whether MBRT/NR increases physical functioning 
in individuals with Long COVID compared with care as 
usual/placebo. 
The Medical Outcome Study 36-item 
short form (SF-36), physical function 
subscore (Jacobsen 2018) 
C13 
To determine whether MBRT/NR increases social functioning in 
individuals with Long COVID compared with care as 
usual/placebo. 
The Medical Outcome Study 36-item 
short form (SF-36), social function 
subscore (Jacobsen 2018) 
 
 
3.2. Additional objectives 
 
In addition to the main intervention effects, this study encompasses several other objectives that fall in 
three main categories (Table 3):  
• Details of the intervention (such as compliance (D1), therapist fidelity (D2), recovery (D3), dose-
response associations (D4), effects of a specific element within the MBRT program (D5), 
interaction effects (D6), subgroup effects (D8 & 9), effect of prior confidence in interventions 
(D10) and success of double-blinding (D11)), all evaluated at T2. 
• Predictors of treatment effects (E1), exploring the associations of a wide array of background and 
T1-variables with outcome variables at T2, cf. paragraph 9. 
• Long-term effects of the intervention, exploiting variables at T3 (F1) as well as linkage with the 
Norwegian Labour and Welfare Administration registry on sick leave (F2). 
 

 
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Table 3. Additional objectives  
 
Objectives 
Outcome measures 
D 
Intervention details  
D1 
To determine compliance with the MBRT/NR interventions.  
Whole blood levels of NAD+; (Trammel 
2016); pills taken vs. pills described ratio; 
patient report of self-directed activities by 
day 25 and at T2. 
D2 
To determine therapist fidelity to the MBRT intervention 
Audio recording and subsequent content 
analyses of a random selection of 
therapist-patient-encounters 
D3 
To determine number of participants meeting recovery threshold 
(population norm) in the four different treatment groups.   
The Medical Outcome Study 36-item 
short form (SF-36), general health 
subscore compared with population 
norm (Jacobsen 2018) 
D4 
To determine dose-response associations within the MBRT/NR 
interventions. 
Previously described primary, secondary 
and exploratory endpoints; whole blood 
levels of NAD+; patient report of self-
directed activities at T2. 
D5 
To determine whether the first medical consultation (“brief 
intervention”) within the MBRT package improves health-related 
quality of life in individuals with Long COVID compared with care 
as usual 
Patient Global Impression of Change 
(PGIC) inventory (Hurst 2004), 
administered to participants in the MBRT 
arm immediately after the first medical 
appointment 
D6 
To determine interaction effects between MBRT and NR 
Previously described primary, secondary 
and exploratory endpoints, analyses of 
interaction effects 
D7 
To determine the safety of MBRT/NR 
Previously described primary, secondary 
and exploratory endpoints, analyses of 
deterioration; clinical investigations, 
analyses of abnormal findings; analyses 
of adverse events; analyses of health 
care contacts and treatment initiations 
D8 
To determine whether MBRT/NR has differential effects in 
subgroups of patients with Long COVID adhering to the Fukuda-
definition (Hickie 2006) of PIFS or not 
Previously described primary, secondary 
and exploratory endpoints, analyses of 
subgroup-effects 
D9 
To determine whether MBRT/NR has differential effects in 
subgroups of patients with high vs. low levels of post-exertional 
malaise (PEM) 
Previously described primary, secondary 
and exploratory endpoints, analyses of 
subgroup-effects 
D10 
To determine whether prior confidence in MBRT and/or NR 
impacts on intervention effects of MBRT 
Previously described primary endpoints; 
customary questions on treatment 
confidence at T1 
D11 
To determine the success of double-blinding of the NR/placebo 
allocation. 
Study physicians’ and participants’ guess 
on NR/placebo allocation at T2 
E 
Predictor analyses 

 
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E1 
To determine predictors of MBRT/NR treatment effects in 
patients with Long COVID 
Previously described primary and 
secondary endpoint, analyses of 
baseline predictors 
F 
Long-term effects 
F1 
To determine whether MBRT/NR has any impact on symptoms, 
function and biological markers at one year follow-up of 
individual with Long COVID compared with care as usual/placebo 
Previously described primary and 
secondary endpoint at 12 months follow-
up (T3). 
F2 
To determine whether MBRT/NR increases work attendance in 
individuals with Long COVID compared with care as usual/placebo 
Linkage with the Norwegian Labour and 
Welfare Administration registry on sick 
leave  
 
 
3.3. Primary estimand 
 
The primary clinical question of interest is: What is the difference in health-related quality of life 
measured by SF-36 (general health subscore) in patients with Long COVID treated with MBRT vs. 
care as usual and NR vs. placebo regardless of discontinuation of investigational intervention for any 
reason?  
 
The primary estimand is described by the following attributes: 
• Population: Patients with a diagnosis of Long COVID, according to the WHO definition (Soriano 
2021).  
• Endpoint: Health-related quality of life measured by general health subscore on SF-36 at 3 months 
follow-up (T2).  
• Treatment condition: The investigational interventions regardless of discontinuation for any reason.  
• Remaining intercurrent events: The intercurrent events “intervention discontinuation for any reason” 
are addressed by the treatment condition of interest attribute. There are no remaining intercurrent 
events anticipated at this time. 
• Population-level summary: Mean difference between treatment conditions 
 
 

 
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4. 
Study Design 
4.1. 
Overall Design 
This 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 (Figure 1). The latter comparison is double blinded.  
 
Eligible participants are individuals (18-70 years) with confirmed Long COVID interfering negatively 
with daily activities (such as work, socially, normal leisure activities, etc.). Participants will be 
recruited from previous COVID-19 studies at our institution, as well as directly through self-referrals 
and referrals from general practitioners and hospital services. A total of 310 participants will be 
enrolled. “Enrolled” means participants’ agreement to participate in a clinical study following 
completion of the informed consent process and screening for eligibility. Potential participants who are 
screened for the purpose of determining eligibility for the study, but do not participate in the study, are 
not considered enrolled, unless otherwise specified by the protocol. A participant will be considered 
enrolled if the informed consent is not withdrawn prior to participating in any study activity after 
screening. 
 
After baseline assessment (T1), the participants will be randomized in 1:1:1:1 probability for four 
treatment groups of approximately equal size: a) MBRT and NR; b) usual care and NR; c) MBRT and 
placebo; d) usual care and placebo. The randomization procedure will utilize a computer-based routine 
for block randomization; block size will vary randomly between 4 and 8. Allocation will be stratified 
by: a) Severity of illness during the acute stage of COVID-19, operationalized as (1) no admission to 
hospital, (2) admission to hospital; and b) Time since acute COVID-19, operationalized as (1) less than 
one year, (2) one year or more.  
 
The intervention period last for three months, followed by primary endpoint assessment (T2). Total 
follow-up time is 12 months (T3). Hence, all participants will be scheduled for three study visits. In 
addition, participants allocated to MBRT will be summoned for an additional 4-6 visits between T1 
(baseline) and T2 (three months follow-up).  
 
For the NR vs. placebo comparison, NR capsules of 250 mg will be given at a fixed dose of 1000 mg 
(ie. four capsules) twice daily in the intervention group, while the control group will receive and 
identical number of identical looking placebo capsules. Treatment duration is 12 weeks (84 days) in 
both groups. 
 
For the MBRT vs. usual care comparison, the MBRT will be delivered as one encounter with a medical 
doctor (“brief intervention”) followed by three face-to-face encounters (alternatively video 
consultations) with a psychiatrist/psychologist trained in the MBRT method. If requested by the 
participants, additional two encounters with a psychiatrist/psychologist may be offered. The entire 
MBRT program will be delivered over a time period of approximately 3 weeks. Also, the participants 
will be provided access to specially developed digital MBRT training resources through Dignio®, an 
internet-based platform for eHealth services. The usual care group will be offered a short self-help 
leaflet and their general practitioners will be provided with results from the standard clinical and 
laboratory examination at baseline (T1); otherwise, no treatment will be given to the usual care-group 
as part of the present study.  
 

 
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Throughout the study, all participants will be able to report adverse events (AE)/serious adverse events 
(SAE) through the Dignio® interface, reducing time delay. The study doctors will report to the Data 
Monitoring Committee weekly about AEs and within 24 hours during weekdays about SAE. Also, 
adverse events (AE) and serious adverse events (SAE) will be charted by questionnaires at two time 
points during the intervention period (two and five weeks after baseline (T1)).  
 
A Data Monitoring Committee for the study will be established.  
 
4.2. 
Scientific Rationale for Study Design 
• Randomized controlled trials is the gold standard for assessment of treatment effects. With this 
design, the untreated participants serve as a control group to the treated participants, and the impact 
of mediating/confounding factors are minimized with randomization.  
• In the present study, testing of NR vs. placebo is double blinded, minimizing the potential bias 
related to placebo effects. The MBRT vs. usual care comparison is impossible to blind due to the 
nature of the treatment. However, during endpoint-evaluation, the responsible researchers will be 
blinded for group allocation  
• SF-36 is a well-validated, generic instrument for assessment of health-related quality of life. As 
Long COVID may encompass a variety of different symptoms, a comprehensive inventory of ill 
health is considered more appropriate than symptom-specific inventories as primary endpoint. Also, 
as Long COVID is defined primarily by patients’ subjective symptom experiences (no biomarker 
has been found as yet), a patient reported outcome measure (PROM) is considered the most 
appropriate primary endpoint.  
• The underlying causes of Long COVID remain elusive, and controversies exists regarding the 
weight given to pure biomedical explanations vs. the potential impact of psychosocial factors 
(Newman 2021). The 2 x 2 factorial design is a convenient way to test two different treatment 
strategies grounded in two different hypothetical models of pathophysiology on the same patient 
population. Hence, treatment effects will be directly comparable and not limited by potential 
selection bias.  
 
4.2.1. 
Patient Input into Design 
The investigational program in this study is based on the observational cohort study entitled Long-
Term Effects of COVID-19 in Adolescents (LoTECA) at Akershus University Hospital (ClinicalTrials 
ID: NCT04686734). Feedback from LoTECA participants has been taken into account when planning 
the design of the present study. In addition, the design has been discussed with representatives of the 
Recovery Norway organization, consisting of individuals having recovered from Long COVID and 
similar post-infective chronic fatigue states. Finally, the design has been discussed with representative 
from the Consumer Advisory Committee of the Collaborative of Fatigue Following Infection (COFFI); 
and international consortium consisting of world-leading researchers on Long COVID and related 
conditions, and headed by the principal investigator of the present study (cf. www.coffi-
collaborative.com).  
 
 

 
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4.3. 
Justification for Dose 
Studies conducted in both healthy human volunteers and mice suggest that a NR dose of 1000 mg twice 
daily (2000 mg in total), in line with the present study, can significantly increase steady-state, whole-
blood levels of NAD+ and effectively stimulate NAD+ metabolism without causing adverse effects 
(Trammel 2016; Martens 2018). Moreover, NR supplementation (500 mg bid) increases brain NAD+ 
levels (Brakedal et al 2022). Furthermore, a study of elimination kinetics indicates that twice-daily 
dosing of NR should be sufficient to achieve a desired clinical outcome (Airhart 2016).  
 
This protocol allows some alteration from the currently outlined dosing schedule (cf. below), but the 
maximum daily dose of NR will not exceed 2000 mg.  
 
4.4. 
End-of-Study Definition 
The end of the study is defined as the date of the last visit (T3) of the last participant in the study. 
A participant is considered to have completed the study if the participant has completed all periods of 
the study including the last visit (T3).  

 
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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be between 18 and 70 years of age at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Participants who have undergone acute COVID-19, confirmed by adhering one of the 
criteria a. and b. below:  
a. Either a positive PCR-test.  
b. Or a positive self-test for SARS-CoV-2 combined with an antibody-pattern from 
serum samples assayed at T1 consistent with previous SARS-CoV-2 infection. 
3. Persistent symptoms at least 6 months following acute COVID-19 without symptom-free 
interval. 
4. Functional disability to an extent that impacts negatively on normal activities (such as 
work attendance, physical exercise, social activities, etc.) 
Informed Consent 
5. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Other chronic illnesses, demanding life situations or concomitant drug use/substance 
abuse that is considered a plausible cause of persistent symptoms and associated 
disability  
2. Sustained organ damage (lung, heart, brain) following acute, serious Covid-19 
3. Pregnancy. 
4. Bedridden. 
Prior/Concomitant Therapy 
N/A 

 
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Other Exclusion Criteria 
5. Insufficient command of Norwegian language (orally and in writing). 
 
 
5.3. 
Lifestyle Considerations 
 
5.3.1. 
Meals and Dietary Restrictions 
No restrictions  
 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
No restrictions.  
 
5.3.3. 
Activity 
No restrictions. 
 
5.3.4. 
Other Restrictions 
Due to scarce data on embryo-fetal developmental toxicity of Nicotine Riboside, participating women 
of fertile age will be recommended to use contraceptives during the intervention phase.  
 
 
5.4. 
Screen Failures 
A screen failure occurs when a participant who has consented to participate in the clinical study is not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the CONSORT publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any SAE. Individuals who do not meet the criteria for 
participation in this study (screen failure) may not be rescreened.  
 
 
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention 
Both acute illness and acute life events may cause a delay in administration study intervention. This is 
accepted but needs to be recorded. 

 
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6. 
Study Intervention(s) and Concomitant Therapy 
Study interventions are all pre-specified, both the dietary supplement NR and the MBRT.   
6.1. 
Study Intervention(s) Administered 
 
Intervention Label 
Nicotinamide 
Riboside 
Placebo 
Mind-body 
reprocessing therapy 
Usual care 
Intervention Name 
NR 
Placebo 
MBRT 
Usual care 
Intervention 
Description 
4 capsules 2 times 
daily 
4 capsules 2 times 
daily 
4-6 face-to-face 
meetings, unlimited 
access to designated 
online resource 
through web-based 
interface 
Brief self-help 
leaflet, otherwise 
care as usual by the 
general practitioner 
Type  
Dietary Supplement 
Placebo 
Psychological 
therapy 
Usual care 
Dose Formulation 
Capsule 
Capsule 
- 
- 
Unit Dose Strength(s) 
250 mg 
- 
- 
- 
Dosage Level(s) 
1000 mg x 2 daily 
4 capsules x 2 daily 
-  
-  
Route of 
Administration 
oral 
oral 
- 
- 
Use 
experimental 
placebo 
experimental  
sham comparator/no 
intervention 
IMP and 
NIMP/AxMP. 
IMP  
IMP 
- 
- 
Sourcing 
Provided locally by 
the study site. 
Provided locally by 
the study site. 
Provided locally by 
the study site. 
Provided locally by 
the study site. 
Packaging and 
Labeling 
Study intervention 
will be provided in a 
pillbox. Each pillbox 
will be labeled as 
required per 
Norwegian precepts, 
including dosage 
instructions 
Study intervention 
will be provided in a 
pillbox. Each pillbox 
will be labeled as 
required per 
Norwegian precepts, 
including dosage 
instructions 
Study intervention 
will be provided 
face-to-face, as well 
as over the internet. 
- 
 
Arm Title 
MBTR and NR 
MBTR and placebo 
Usual care and NR 
Usual care and 
placebo 
Arm Type 
Experimental and 
experimental 
Experimental and placebo 
No intervention 
and 
experimental 
No intervention 
and placebo  
Arm Description 
MBRT: Face-to-face 
encounters with medical 
doctor (1 encounter) and 
psychiatrist/psychologist 
(3-5 encounters) as well 
as access to designated 
digital resources over a 3 
months period.  
 
NR 1000 mg x 2 daily for 
3 months. 
MBRT: Face-to-face 
encounters with medical 
doctor (1 encounter) and 
psychiatrist/psychologist 
(3-5 encounters) as well 
as access to designated 
digital resources over a 3 
months period.  
 
Placebo capsules x 2 daily 
for 3 months. 
No intervention: 
Participants will 
receive a small 
self-help brochure, 
and check-ups as 
usual at the 
general 
practitioner. 
 
NR 1000 mg x 2 
daily for 3 months. 
No intervention: 
Participants will 
receive a small 
self-help brochure, 
and check-ups as 
usual at the 
general 
practitioner. 
 

 
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6.1.1. 
Medical Devices 
N/A 
 
6.2. 
Preparation, Handling, Storage, and Accountability 
• ChromaDex, Inc., USA will supply both nicotinamide riboside (NR) and placebo capsules and ship 
them to the Akershus University Hospital (Ahus). Placebo pills contain microcrystalline cellulose 
within a vegetarian capsule..  
• NR and placebo capsules will be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited to 
the authorized site staff. 
• The investigator is responsible for randomization of the participants and for participant information 
about NR/placebo.  
 
 
6.3. 
Assignment to Study Intervention 
The study consists of four treatment arms. In addition, two stratification variables are defined: initial 
severity (not hospitalized vs. hospitalized) of acute COVID-19, and time since (< vs. ≥ 12 months) 
acute COVID-19, resulting in four strata. For each strata, block randomised series will be created by a 
computer-based algorithm (1:1:1:1 allocation to the four treatment arms, block size to vary between 4 
and 8). After baseline assessment at T1, all included participants will be designated to a specific strata 
and provided with an envelope containing the allocation to study arm.  
 
 
6.4. 
Blinding 
For the NR vs. placebo comparison, both researchers and participants are blinded throughout the course 
of the study. The relevant capsules are labelled A and B; the encoding is only known by the 
biostatistician in the Independent Data Monitoring Committee. As a quality check of blinding, a 
questionnaire item at T2 will prompt the participants as well as researchers to guess whether 
participants received NR or placebo, and the relationship between guessed and factual allocation will 
be subjected to statistical testing of randomness. Due to the nature of the intervention, the allocation of 
participants to MBRT or usual care will not be blinded.  
 
 
6.5. 
Study Intervention Compliance 
NR vs. placebo 
• At therapy initiation, each participant will be supplied with a defined number of capsules. The 
residual number at T2 will be counted, and an index of compliance will be calculated 
Placebo capsules x 
2 daily for 3 
months. 

 
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• Compliance will also be assessed by comparing the concentration of NAD+ in whole blood at T2 
and T1. 
MBRT vs. usual care 
• The therapists will record any deviation from planned face-to-face therapies 
• Within the web-based interface of Dignio®, the participants will record the number of different self-
directed activities per week prompted by the designated digital resources at two time points: 25 days 
after T1 and at T2.  
• All therapy sessions will be audio-recorded. After completion of all interventions, a random 
selection of 20 % of the recordings will be analyzed to assess therapeutic fidelity.  
• A total of 5 % of all therapy sessions will be video-recorded (based upon separate consent from the 
patients), and used for continuous supervision of the therapists during the course of the study.  
 
 
6.6. 
Dose Modification 
This study is using a fixed dose of NR of 1000 mg x 2. In individuals complaining of non-serious side 
effects that may be attributed to the treatment, the dose can halved (NR of 500 mg x 2) at the 
researchers’ discretion.  
 
6.6.1. 
Retreatment Criteria 
N/A 
 
 
6.7. 
Continued Access to Study Intervention after the End of the Study 
If one of the interventions is found to be beneficial, participants in the non-intervention group who 
suffer from a sustained Long COVID diagnosis will be offered the same treatment after completion of 
the study. Otherwise, no other access to treatments will be offered within the framework of the present 
study.  
 
 
6.8. 
Treatment of overdose 
For this study, any dose of NR greater than 300 mg/kg within a 24-hour time period will be considered 
an overdose (Marniescu 2020). In the event of an overdose, the treating physician should: 
• Evaluate the participant to determine, in consultation with the Data Monitoring Committee, whether 
study intervention should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities as medically 
appropriate and at least until the next scheduled follow-up. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
 
 
6.9. 
Prior and Concomitant Therapy 
Therapy initiated prior to inclusion in the present study may be continued as long as it complies with 
the inclusion and exclusion criteria (cf. above). During the active intervention period (from T1 to T2), 

 
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participants should not undertake any concomitant therapy for Long COVID. Therapies for other 
conditions should be evaluated by the investigators on a case-by-case basis. In the period from T2 to 
T3, concomitant therapy is generally allowed, except for the therapies tested in the present study (NR 
and MBRT).  
 
6.9.1. 
Rescue Medicine 
N/A 
 

 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study intervention. If 
study intervention is permanently discontinued, the participant should, if at all possible, remain in the 
study to be evaluated at assessment points. The final decision on discontinuation will be taken by the 
principal investigator (PI) of the study. The Data Monitoring Committee will be notified without undue 
delay.  
 
7.1.1. 
Liver Chemistry Stopping Criteria 
N/A 
 
7.1.2. 
QTc Stopping Criteria 
N/A 
 
7.1.3. 
Temporary Discontinuation 
Discontinuation of intervention may be considered at the PI’s discretion and will routinely be applied 
after a registered SAE. 
 
7.1.4. 
Rechallenge 
N/A 
 
7.1.4.1. 
Study Intervention Restart or Rechallenge After Liver Stopping Criteria Are Met 
N/A 
 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at the participant’s own request for any 
reason (or without providing any reason). 
• A participant may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons.  
• At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
• The participant will be permanently discontinued from the study intervention and the study at that 
time. 
• The participant can withdraw consent for disclosure of future information. 
• If a participant withdraws from the study, the participant may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
 
 

 
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7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. The following actions must be taken if 
a participant fails to return to the clinic for a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as possible, 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain 
whether the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make every effort 
to regain contact with the participant (where possible, three telephone calls, and if necessary, a 
certified letter to the participant’s last known mailing address). These contact attempts should be 
documented in the participant’s medical record. 
• Should the participant continue to be unreachable, the participant will be considered to have 
withdrawn from the study.  

 
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8. 
Study Assessments and Procedures 
 
8.1. 
Investigational program 
 
8.1.1. 
Preparations and clinical examination 
At T1, T2 and T3, all participants will undergo a structured investigational program at the MINIRICO 
study center at Akershus University Hospital. They will be offered local anesthetic ointment (EMLA®, 
AstraZeneca) to apply on the antecubital vein one hour before arriving, to avoid the pain of venous 
puncture. Finally, they will be instructed to bring a spot urine sample in a sterile container. 
 
The clinical interview will include questions on country of origin/ethnicity as well a chronic diseases 
and permanent use of pharmaceuticals. Examination will encompass a structured review of organ 
systems, particularly focusing on respiratory (stridor, wheezing, retractions, crackling sounds), 
cardiovascular (murmur) and neurological (focal signs) abnormalities. Weight, height, blood pressures 
(sitting position, non-dominant arm), blood oxygen saturation (SaO2), and tympanic temperature will 
be recorded. The urine sample will be assayed with a Multistix 5 (Siemens Healthcare, Erlangen, 
Germany); also, a pregnancy test will be performed of all women aged 18 to 50 years (T1 and T2 only).   
8.1.2. 
Functional testing 
Spirometry  
Spirometry will be conducted to measure the forced vital capacity (FVC) and the forced expiratory 
volume in one second (FEV1) (EasyOne® Air spirometer, EasyOne Connect software, NDD 
Medizintechnic AG, Switzerland). The ratio of FEV1/FVC will be calculated. Procedures will be 
executed according to the American Thoracic Society and European Respiratory Society guidelines, 
and recordings that do not adhere to technical quality requirements will be excluded from the main 
analysis (Graham 2019). The Global Lung Function Initiative 2012 network reference values will be 
used to calculate the percentage of predicted values and the lower limit of normal (LLN) (Quanjer 
2012). 
 
ECG recording and autonomic cardiovascular control 
A 5-minute ECG recording will be performed applying The Bittium Faro 360® device (Bittium 
Corporation, Oulu, Finland). During recording, participants will be laying supine in a dark room with 
calm surroundings.  
 
Recordings will be analyzed using manufacturer developed software, providing automatic R-wave 
detection and exclusion of arrhythmias (including ectopic beats). Heart rate variability (HRV) indices 
will be calculated in the time domain, as well as in the frequency domain after Fast Fourier 
Transformation of the time series, according to international standards (Task Force 1996). Computed 
time domain indices include SDNN (the standard deviation of all RR-intervals), pNN50 (the proportion 
of successive RRIs with a difference greater than 50 ms), and r-MSSD (the square root of the mean 
square differences of successive RRIs). In the frequency domain, power densities will be computed in 
the low-frequency (LF) band (0.04-0.15 Hz) and the high-frequency (HF) band (0.15-0.5 Hz), and 
expressed both in absolute (LFabs, HFabs) and normalized units, where LFnorm= LFabs /(LFabs + HFabs) 
and HFnorm= HFabs /(LFabs + HFabs). In addition, the LFabs/HFabs ratio will be computed.  
 

 
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Vagal (parasympathetic) activity is considered the main contributor to HF-variability of heart rate, 
whereas both vagal and sympathetic activity contributes to LF-variability (Saul 1990; Pagani 1986). 
The LF/HF ratio is considered an index of sympathovagal balance. 
 
Cognitive function tests 
All cognitive function tests will be carried out by trained examiners in a separate room with calm 
surroundings. The Digit Span Test will be adopted from the Wechsler Adult Intelligence Scale (WAIS), 
4th edition (WAIS-IV). This test is used for verbal and auditory working memory assessment. A string 
of random digits is read aloud by the examiner. The first string consists of two random numbers, and 
for every other string, one more number is added. The digit span forward mode requires the test subject 
to repeat the digits in the same order as they are presented; in the digit span backward mode, digits are 
repeated in reverse order. Each correctly repeated string is scored one point. The test is discontinued 
when two strings of equal length are answered incorrectly. Sum scores for digit span forward and 
backward, as well as total sum score, will be computed. 
 
A test of verbal learning, delayed recall, and recognition is adopted from the Hopkins Verbal Learning 
Test-Revised (HVLT-R) (Benedict 1998). The examiner read aloud a list of 12 words and the 
participant is asked to repeat as many words as possible in three consecutive trials. An index of verbal 
learning memory will be computed as the sum score of remembered words (ranging from 0 to 36) 
across the three trials. After 20 minutes, the examiner asks the participants to report as many words as 
possible; an index of delayed verbal memory is computed as the number of words the test subject were 
able to recall correctly (ranging from 0 to 12). Finally, a total of 24 words are read aloud by the 
examiner, of which 12 are identical to the previous list of words; the number of correctly recognized 
and falsely recognized words is recorded separately (both indices ranging from 0 to 12).  
 
A trail-making test asking the participants to draw lines between numbers and letters in increasing 
order will be performed. The trail-making test is primarily a test of executive functions.  
8.1.3. 
Sampling of biological specimens and laboratory assays 
Sampling and biorepository procedures  
Blood samples will be drawn with participants laying in a supine position using an antecubital vein; if 
requested by the participants, local anaesthetic ointment (EMLA®) will be applied for at least 60 
minutes but removed 15 minutes prior to sampling.  
 
Blood samples will immediately undergo further preparations in order to obtain aliquots of plasma, 
serum, whole blood, RNA and viable Peripheral Blood Mononuclear Cells (PBMC)). Thereafter, blood 
derived material not subjected to further analyses will be transferred to a biorepository adjacent to the 
study centre (EpiGen laboratories, Akershus University Hospital, Norway), and stored at -80oC or -
150oC, as appropriate.  
 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 150 mL. Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples. 
 
Inflammatory markers 
EDTA whole blood samples will be placed on ice-water for 5-60 minutes. Followingly, plasma will be 
separated by centrifugation (2200 g, 10 min.) and frozen at –80 °C until assayed. Plasma levels of 

 
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growth-differentiation factor (GDF)-15, interleukin-6 and C-reactive protein (CRP) will be measured 
using an automated immunoassay from Roche Diagnostics. 
 
SARS-CoV-2-antibodies 
Sera from all participants will be screened for IgG antibodies against the receptor-binding domain 
(RBD, Wuhan) as well as the nucleocapsid antigen of the SARS-CoV-2 virus, using automated 
immunoassays from Roche Diagnostics or Abbott Diagnostics. 
 
Routine blood analyses 
Routine blood markers will be assayed at the accredited laboratory at Akershus University Hospital, 
Norway, and include the following: Haemoglobin; Leukocytes with differential count; Platelets; CRP; 
Ferritin; Alanine transaminase (ALT); Gamma-glutamyltransferase (GGT); Lactate dehydrogenase 
(LDH); Albumin; N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP); Troponin T; 
Creatine kinase (CK); Glucose; Glycated haemoglobin (HbA1C); Bilirubin; D-dimer; International 
Normalized Ratio (INR); Urea; Creatinine; Natrium; Potassium; Calcium; Vitamin B12; Folic acid; 
Vitamin D; Thyroid-stimulating hormone (TSH); Thyroxine; Cortisol; IgG (total); IgM (total); IgA 
(total); Blood gases (venous sample); SARS-CoV-2 anti-nucleocapsid, total antibody titer (IgM+IgG).  
8.1.4. 
Questionnaires 
A composite questionnaire consisting of validated inventories will be used to chart clinical symptoms, 
personality traits, social factors as well as basic demographic and constitutional variables. An overview 
is provided in Table 1. The questionnaire will be administered digitally using the “Nettskjema”-tool 
administered by the Services for Sensitive Data at the University of Oslo 
(https://www.uio.no/english/services/it/research/sensitive-data/index.html). This tool ascertains that all 
items are completed before submission to a dedicated and secured server area where scores are 
automatically computed following a predefined scoring algorithm. All participants will answer the 
questionnaire using a dedicated computer at our study center as part of the investigational program at 
baseline and follow-ups. 
 
Table 1. Composite questionnaire overview: Constructs, inventories and scoring procedures  
Construct(s) 
Name of inventory 
Description and scoring procedures 
A. BACKGROUND AND DEMOGRAPHICS 
 
1. Household, 
socioeconomic level 
Not applicable 
Household members; parents’ occupation; the international socio-economic 
index (ISEI) of occupational status is used to score socio-economic level 
(Ganzeboom 1992) 
2. Smoking, alcohol, 
drugs 
Not applicable 
Alcoholic beverages, illicit drugs, smoking; answered on a 5-point Likert 
scale, where 1 is “never” and 5 is “every day/almost every day”. 
3. Physical activity 
Not applicable 
Answered on a 5-point Likert scale, where 1 is “a lot less active than peers” 
and 5 is “a lot more active than peers”. 
4. Diseases 
Not applicable 
Chronic diseases; chronic disease among family members; undergone acute 
COVID-19 (only asked at follow-up) 
5. Vaccines  
Not applicable 
Received vaccination against COVID-19 (number of dosages, manufacturer) 
B. UNEXPECTED/ADVERSE EVENTS  
1. Events 
Not applicable 
A total of 13 items addressing specified adverse events (including more 
symptoms, more health problems in general, depressive episodes, suicidal 

 
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thoughts, increased disability) and spontaneous contact with health services, 
as well as free text comments 
C. SYMPTOMS AND DISABILITY 
 
1. Fatigue  
Chalder Fatigue 
Questionnaire (CFQ) 
A total of 11 items scored on 4-point Likert scales. In order to obtain a 
continuous variable, each item will be scored 0-3 where 0 is “less than usual” 
and 3 is “much more than usual”; then, a total sum score across all items is 
obtained ranging from 0 to 33, where higher scores indicate more fatigue 
(Chalder 1993). In addition, bimodal scoring (0-0-1-1) of each item will be 
performed; a total sum score across all items of 4 or higher is defined as 
fatigue caseness.  
2. Clinical 
symptoms of post-
COVID-19 condition 
and PPIS 
CDC symptom 
inventory for Chronic 
Fatigue Syndrome 
 
A total of 30 items addressing frequency of specific symptoms since falling ill 
from acute COVID-19 on 5-point Likert scales, where 1 is “never” and 5 is “all 
the time” (Wagner 2005). At follow-up, the questions will be slightly 
rephrased in order to address symptom frequency during the last months..  
3. Post-exertional 
malaise (PEM) 
PEM items from the 
DePaul Symptom 
Questionnaire 
A total of five items addressing frequency of PEM symptoms on 5-point Likert 
scales, where 0 is “never” and 4 is “all the time”; answers are then averaged 
across all items and multiplied with 25 to get a 100 point scoring scale where 
higher scores indicate more PEM (Bedree 2019) 
4. Sleep 
disturbances 
Karolinska Sleep 
Questionnaire (KSQ) 
A total of 12 items addressing frequency of sleep disturbances on 6-point 
Likert scales, where 1 is “never” and 6 is “all the time”; then, the scoring is 
reversed, and total sum score is computed across all items ranging from 12 
to 72, where lower scores indicate more sleep disturbances (Akerstedt 
2008). Accordingly, indexes for insomnia, awakening problems, and 
sleepiness will be computed as sum scores across relevant items. 
5. Pain 
Brief Pain Inventory 
(BPI) 
A total of four items addressing different aspects of pain on 10-point Likert 
scales, where 1 is “no pain” and 10 is “worst pain imaginable”; total sum 
score is computed across all items ranging from 4 to 40, where higher scores 
indicate more pain. (Klepstad 2002) 
6. Dyspnoea 
Medical Research 
Council dyspnoea 
scale 
A single item addressing dyspnea on a 5-point Likert scale, where 1 is 
“breathless during strenuous exercise” and 5 is “too breathless to leave the 
house” (Bestall 1999) 
7. Depression and 
anxiety symptoms 
Hospital Anxiety and 
Depression 
Symptoms (HADS) 
A total of 14 items addressing different symptoms of depression and anxiety 
on 4-point Likert scales scored 0 – 3; for eight of the items, scoring is 
reversed, after which total sum score is computed ranging from 0 to 42, 
where higher scores indicate more symptoms of depression and anxiety 
(Zigmond 1983). Accordingly, separate indexes for depression and anxiety 
will be computed as sum scores across relevant items (seven each). 
8. Quality of life  
36-Item Short Form 
Survey (SF-36). 
A total of 36 items, scored on Likert scales and recoded to achieve 100 point 
scales (higher score means better quality of life); average scores are 
reported. Eight subdomains: Physical functioning; Role limitations due to 
physical health; Role limitations due to emotional problems; Energy/fatigue; 
Emotional well-being; Social functioning; Pain; General health (Ware 1992) 
9. Impression of 
change 
Patient Global 
Impression of Change 
(PGIC) 
A single 7-point Likert scale where patient rate their impression of change in 
health status from “no change/worsening” to “very much improved” (Guy 
1976; Perrot 2019) 
10. Miscellaneous 
Not applicable 
• One item addressing avoidance behavior on a 10-point Likert scale, where 
higher scores indicate more avoidance tendency.   
• One item addressing school/work absenteeism as number of totally absent 
days during the last month.  
D. PSYCHOLOGICAL TRAITS AND SOCIAL FACTORS 
1. Neuroticism 
NEO Five-Factor 
Inventory-30 (NEO-
FFI-30) 
A total of six items making up the neuroticism axis will be included and 
scored on 5-point Likert scales where 0 is “disagree completely” and 4 is 
“agree completely”; total sum score across all items will be computed ranging 

 
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from 0 to 24, where higher scores indicate stronger neuroticism tendencies 
(Körner 2008) 
2. Worrying 
tendencies 
Penn State Worry 
Questionnaire 
(PSWQ) 
A total of 16 items addressing worrying tendencies will be scored on 5-point 
Likert scales where 1 is “disagree completely” and 5 is “agree completely”; 
scoring will be reversed on five items, after which the total sum score across 
all items is computed ranging from 16 to 80, where higher scores indicate 
stronger worrying tendencies (Pallesen 2006) 
3. Loneliness 
UCLA Loneliness 
Scale 
A total of 20 items addressing loneliness will be scored on 4-point Likert 
scales where 1 is “never” and 4 is “always”; scorings are reversed on nine 
items, after which the total sum score is computed ranging from 20 to 80, 
where higher scores indicate more loneliness (Russel 1980) 
 
8.2. 
Administrative and General/Baseline Procedures 
Recruitment and screening for eligibility 
• The project will be announced at institutional website, at social media, and at collaborating health 
service institutions (such as general practitioners and hospital outpatient clinics) providing services 
for Long COVID patients. Also, Long COVID patients participating in prior COVID-19 research 
projects at our institution will be directly approached if permitted by the patient consent given in the 
particular projects and provided with general project information.  
• Long COVID patient who are interested in participating will contact the MINIRICO study center by 
a dedicated phone number or email. A research secretary will provide general information orally and 
in writing, as well as conduct a standardized screening interview of eligibility of those who express 
a potential interest in participating in the trial. Questions in the interview include how and when the 
initial COVID-19 infection was established, the presence of persistent symptoms, the degree of 
functional impairment, co-morbidities and/or pharmaceuticals that may explain persistent 
symptoms, presence of permanent organ sequels after acute COVID-19, pregnancy, and command 
of Norwegian language. Patients that are considered eligible will be provided with the patient 
consent form, and a time point for baseline encounter will be agreed upon.  
 
Inclusion and randomization 
• Upon arriving for baseline assessment (T1), the eligibility of the possible participant will be 
assessed by the study doctor. Inclusion will be finalized by the patient signing the consent form, 
followed by randomization to one of the four treatment arms. 
 
8.3. 
Efficacy Assessments 
Efficacy assessments are described in paragraph 3. In short:  
• Primary endpoint is the SF-36 general health sub score at T2, cf. Table 2 above.  
• Secondary endpoints are inflammatory marker (hsCRP), executive function (Trail Making Test part 
B), fatigue, dyspnea, global impression of change in symptoms, function and quality of life, and 
incremental cost-effectiveness ratio.  
• Exploratory endpoint include PROMs as well as blood biomarkers and functional test results, as 
specified in paragraph 3. 
 
 

 
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8.4. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA. 
 
8.4.1. 
Physical Examinations 
The physical examination will include assessments of all organ systems as well as height and weight at 
all study visits, cf. above. Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
 
8.4.2. 
Vital Signs 
Vital signs will include tympanic temperature, systolic and diastolic blood pressure, heart rate, 
respiratory rate, and peripheral oxygen saturation (SaO2). Three readings of blood pressure and heart 
rate will be obtained. The first reading should be rejected, and the second and third reading should be 
averaged to give the measurement to be recorded. 
 
8.4.3. 
Electrocardiograms 
A 5-minute 5-lead ECG recording will be performed applying The Bittium Faro 360® device (Bittium 
Corporation, Oulu, Finland), as described in paragraph 8.1 and outlined in the SoA (see Section 1.3). 
 
8.4.4. 
Clinical Safety Laboratory Tests 
• See paragraph 8.1 for the list of clinical laboratory tests to be performed, and the SoA (Section 1.3) 
for the timing and frequency. 
• The investigator must review the laboratory results, document this review, and record any clinically 
significant changes occurring during the study as an AE. The laboratory results must be retained 
with source documents.  
• Abnormal laboratory findings associated with the underlying disease are not considered clinically 
significant unless judged by the investigator to be more severe than expected for the participant’s 
condition. 
• All laboratory tests with values considered clinically significantly abnormal during participation in 
the study or within 9 months after the last dose of study intervention should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor. 
o 
If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the participant will be 
referred to further investigations at the hospital (to appropriate specialists).  
o 
All protocol-required laboratory tests, as defined paragraph 8.1, must be conducted in 
accordance with the laboratory manual and the SoA (Section 1.3). 
o 
If laboratory values from non-protocol-specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
significant by the investigator (eg, SAE or AE or dose modification), then the results must be 
recorded. 
 
8.4.5. 
Pregnancy Testing 
All female participants aged 18 – 50 years will have a urine pregnancy test at baseline and at 3 months 
(cf. the SoA, Section 1.3). Due to scarce data on embryo-fetal developmental toxicity of Nicotine 
Riboside, participating women of fertile age will be recommended to use contraceptives during the 
intervention phase.  

 
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8.4.6. 
Suicidal Ideation and Behavior Risk Monitoring 
All participants will be monitored appropriately and observed closely for suicidal ideation and behavior 
(SIB) or any other unusual changes in behavior, especially at the beginning and end of the course of 
intervention. Participants who experience signs of SIB should undergo a risk assessment. All factors 
contributing to SIB should be evaluated and consideration should be given to discontinuation of the 
study intervention.  
 
Both baseline assessment of suicidal ideation and behavior and intervention-emergent suicidal ideation 
and behavior will be assessed at baseline and follow-ups. In addition, suicidal ideation and behavior 
will be closely monitored during the intervention stage using the DIGNIO® digital interface. Finally, 
as a separate safety measure, participants scoring 15 or more on the HADS depression subscale 
(corresponding to possible serious depression) at baseline or follow-up will be directly approached by 
the investigators and asked about suicidal ideation and behavior, and eventually referred to relevant 
health services.  
 
8.5. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and Other Safety 
Reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in the 
Appendix. The definitions of unsolicited and solicited adverse events can be found in Appendix. 
The investigator and any qualified designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up all AEs OR 
AEs that are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the interventions. This includes events reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and transmitting SAE reports are provided in Appendix. 
 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs and AEs will be collected from the start of study intervention until the follow-up visit at the 
timepoints specified in the SoA (Section 1.3). Medical occurrences that begin before the start of study 
intervention but after obtaining informed consent will be recorded as medical history/current medical 
conditions, not as AEs. 
 
8.5.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. When submitted to the 
study, participants will be informed that they should report possible AEs and SAEs directly to the study 
doctors through the DIGNIO® digital interface. In addition, all participants will be reminded to report 
AE/SAE occurrences within DIGNIO®. Finally, AE/SAE will be charted by the questionnaire at 
follow-ups. 
 
8.5.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.4.8) will be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is lost to 

 
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follow-up (as defined in Section 7.3). Further information on follow-up procedures is provided in 
Appendix. 
 
8.5.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the data monitoring committee of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
 
8.5.5. 
Pregnancy 
• Women with a positive pregnancy test at T1 will not be included in the study. Due to scarce data on 
embryo-fetal developmental toxicity of Nicotine Riboside, participating women of fertile age will be 
recommended to use contraceptives during the intervention phase.  
• Despite these precautions, if a pregnancy is reported during the course of the study, the investigator 
will record pregnancy information on the appropriate form.  
• Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention and be withdrawn from the study. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant will be followed to determine the outcome of the pregnancy.  
• Any poststudy pregnancy-related SAE considered reasonably related to the study intervention by the 
investigator will be reported to the local authorities as described in Section 8.4.4. While the 
investigator is not obligated to actively seek this information in former study participants, he or she 
may learn of an SAE through spontaneous reporting. 
 
8.5.6. 
Cardiovascular and Death Events 
Cardiovascular events and death events occurring during the course of the study will be regarded as a 
SAE and handled accordingly.  
 
8.5.7. 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs or 
SAEs 
There are several disease-related events (DREs) in the acute face of a SARS-CoV-2 infection (eg. 
Acute Respiratory Distress Syndrome and clotting abnormalities). However, no present evidence 
suggests that DREs may appear more than six months after the acute infection (cf. inclusion criteria for 
the present study), and no specific DRE has been reported with Long COVID. Thus, there are no 
known DREs that are associated with the underlying disease in this study.  
 
8.5.8. 
Adverse Events of Special Interest 
N/A 
 
8.5.9. 
Medical Device Deficiencies 
N/A 
 
8.5.9.1. 
Time Period for Detecting Medical Device Deficiencies 
N/A 

 
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8.5.9.2. 
Follow-up of Medical Device Deficiencies 
N/A 
 
8.5.9.3. 
Prompt Reporting of Device Deficiencies to the Sponsor 
N/A 
 
8.5.9.4. 
Regulatory Reporting Requirements for Device Deficiencies 
N/A 
 
 
8.6. 
Pharmacokinetics 
• Whole blood samples of approximately 2 mL will be collected for measurement of whole blood 
concentrations of NAD+ as specified in the SoA (Section 1.3).  
• Samples will be used to evaluate the pharmacokinetics of NR. Samples collected for analyses of 
NAD+ concentration may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. 
• Intervention concentration information will not be reported to investigative sites or blinded 
personnel until the study has been unblinded. 
 
 
8.7. 
Pharmacodynamics 
N/A 
 
 
8.8. 
Genetics 
Whole blood samples for potential later genetic analyses will be collected and stored at -80 oC. 
However, genetic analyses are not part of the present study, and separate approbation will be sought for 
future genetic analyses.  
 
8.9. 
Biomarkers 
A detailed overview of biomarker analyses are given in paragraph 8.1, above. In addition, biological 
specimens will be stored in a biorepository enabling further research projects (that would require 
separate approbations) as follows:   
 
 
 
Blood samples 
Aliquots 
Serum  
4 x 500 µL 
EDTA-Plasma 
6 x 500 µL 
EDTA-Whole Blood (for 
DNA isolation) 
4 x 900 µL 

 
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CPT (for viable PBMC 
isolation) 
 4 x 1mL citrate plasma + 2 x 1 mL 
PBMC   
PAX (mRNA isolation) 
 
 
8.10. 
Immunogenicity Assessments 
N/A 
 
 
8.11. 
Health Economics 
Incremental cost-effectiveness ratio is defined as a secondary endpoint, using the 36-item short form 
(SF-36) general health sub score to determine quality-adjusted life years (cf. paragraph 3).  
 
 
8.12. 
Registry linkage 
In order to a) ascertain the diagnosis of PACS and b) to explore predictors of intervention effects (cf. 
paragraph 3 and 9), linkage with the following existing registries will be established: ‘Norsk 
pasientregister’, ‘Vaksine-registeret Sysvak’, ‘Legemiddelregisteret’, ‘Meldesystem for smittsomme 
sykdommer (MSIS)’ and ‘Pandemiregisteret’.  
 
For assessment of work attendance, linkage with the Norwegian Labour and Welfare Administration 
registry on sick leave will be established.  
 
 
8.13. 
Qualitative substudy 
A qualitative substudy will be implemented in the MINIRICO design, with the aim of exploring 
participants’ experiences with the MBRT intervention. A total of 20 participants who have been 
allocated to MBRT will be recruited after completion of the intervention period (i.e., after T2). These 
participants will undergo semi-structured interviews which will be subsequently transcribed verbatim 
and subjected to qualitative thematic analyses.  
The qualitative substudy is further detailed in a separate research protocol that has been approved by 
the Regional Ethics Committee. Inclusion in the substudy is based on separate informed consent (i.e., 
independent on consent to participation in MINRICO). The interviews and subsequent analyses are 
conducted by researchers not otherwise involved in MINIRICO.  

 
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9. 
Statistical Considerations 
The analysis and reporting will be done on all data from all participants at the time the study ends. 
The statistical analysis plan will be finalized prior to unblinding and it will include a more technical 
and detailed description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
 
 
9.1. 
Statistical Hypotheses 
In this study, there are two primary objectives:  
1. To determine whether MBRT increase health-related quality of life in individuals with Long 
COVID compared with care as usual. Thus, the null hypothesis to be tested in relation to the first 
primary estimand is as follows: 
• Null hypothesis: MBRT is not different from care as usual with respect to the achievement of an 
increase in health-related quality of life at 3 months follow-up (T2). 
vs.  
• Alternative hypothesis: MBRT is different from care as usual with respect to the achievement of 
an increase in health-related quality of life at 3 months follow-up (T2). 
2. The second objective is to determine whether NR increase health-related quality of life in 
individuals with Long COVID compared with placebo Thus, the null hypothesis to be tested in 
relation to the second primary estimand is as follows: 
• Null hypothesis: NR is not different from placebo with respect to the achievement of an 
increase in health-related quality of life at 3 months follow-up (T2). 
vs.  
• Alternative hypothesis: NR is different from placebo with respect to the achievement of an 
increase in health-related quality of life at 3 months follow-up (T2).. 
 
9.1.1. 
Multiplicity Adjustment 
For the primary endpoint analyses, the level of significance is set at α=0.05. A testing procedure that 
controls the family wise error rate (FWER) at the overall 5% level will be applied for efficacy 
evaluation of the six secondary endpoints as well as a potential interaction effects between the two 
interventions. However, as previous research indicates significant correlation between several PROMs 
in Long COVID patients (Selvakumar 2022), the Bonferroni correction method is not considered to be 
the best solution for FWER correction; rather, a resampling procedure such as the one suggested by 
Romano and Wolf will be applied (Romano 2005). 
 
As for the exploratory endpoints, no multiplicity adjustments will be carried out.  
 
9.2. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Full analysis set (FAS) 
• 
All randomized participants.  

 
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Participant Analysis Set 
Description 
Safety analysis set (SAS) 
• 
All participants who are exposed to investigational intervention. 
Per-protocol analysis set (PPAS) 
• 
All randomized participants that completed the treatment period without 
any of the following protocol deviations: Interruption of therapy; Lost to 
follow-up (including participant withdrawal); Primary endpoint 
measurements missing; Diagnosed with another chronic disorder during 
the study period; Experiencing a severe illness or trauma during the 
study period; Commencing other treatment for Long COVID during the 
study period; Low compliance with the NR/placebo intervention; Low 
compliance with the MBRT intervention.  
The full analysis set will be used to analyze endpoints related to the efficacy objectives and the safety 
analysis set will be used to analyze the endpoints and assessments related to safety. Per-protocol 
analyses will be reported as sensitivity analyses.  
 
For the efficacy analyses, participants will be included in the analyses according to the planned 
investigational intervention; whereas for safety analyses, participants will be included in the analyses 
according to the investigational intervention they actually received. 
 
9.3. 
Statistical Analyses 
 
9.3.1. 
General Considerations 
Variables will be reported with parametric or non-parametric descriptive statistics, eventually 
frequency tabulation, as appropriate. All statistical tests will be carried out two-sided. Generally, a p-
value ≤ 0.05 is considered statistically significant.  
 
9.3.2. 
Primary Endpoint Analysis 
 
9.3.2.1. 
Definition of endpoint(s) 
The primary endpoint is The Medical Outcome Study 36-item short form (SF-36), general health 
subscore. This variable is usually distributed close to a normal distribution; thus, parametric statistics 
are applicable.  
 
9.3.2.2. 
Main Analytical Approach 
A general linear model (ANCOVA) applied on the FAS will be used for analyses of treatment effect; 
the baseline value of the primary endpoint as well as stratification variables from the randomization 
procedure will be included as covariates. Two statistical tests will be carried out (one for each of the 
primary hypothesis related to each treatment comparison). For each statistical analysis, the net 
intervention effect (the mean difference between groups at T2) will be calculated from the parameters 
of the fitted general linear model and reported with 95 % confidence interval. Also, interaction effects 
will be investigated.  
 
9.3.2.3. 
Sensitivity analysis  
A similar analytic approach as described in 9.3.2.2. applied on the PPAS will be performed as a 
sensitivity analysis.  

 
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9.3.2.4. 
Supplementary analysis  
Please cf. the Statistical Analysis Plan for details  
 
9.3.3. 
Secondary Endpoints Analysis 
A similar analytic approach as described in 9.3.2.2. applied on both the FAS and the PPAS will be 
performed as for all secondary endpoints analyses 
 
9.3.4. 
Exploratory Endpoint Analysis 
Exploratory endpoint analyses will depend upon variable characteristics as well as hypotheses 
developed form the primary and secondary endpoint analyses; thus, no detailed specification is feasible 
at the present stage. 
 
9.3.5. 
Safety Analyses 
Safety data will be summarized descriptively through appropriate data tabulations and descriptive 
statistics. 
 
9.3.6. 
Other Analyses 
 
9.3.6.1. Predictors of treatment effects 
A prediction analysis of treatment effects will feature a methodological set-up similar to a recent  
observational cohort study of COVID-19 patients (Selvakumar 2022), exploring associations between a 
wide range of background and T1-variables (independent variables) and T2-effector variables 
(dependent variables) by regression analyses. The PPAS will be applied in these analyses. The 
independent variables include: 
• Previous infectious diseases: COVID-19 diagnosed by PCR-test (date, genetic variant), other 
infectious events one year prior to inclusion 
• Previous immunizations: Vaccination against COVID-19 (date(s), type(s)), other vaccinations one 
year prior to inclusion. 
• Previous and current medical history: Diagnoses of other chronic diseases, current medication 
• Severity of acute COVID-19: Hospitalization (days), intensive care unit admission (days), 
respiratory support, cardiovascular support, neurological sequels, thromboembolic events, 
immunological and infectious markers during hospital stay (CRP, viral replication numbers). 
• Current clinical symptoms and functional disability  
• Psychological traits (neuroticism, worrying tendencies) and social features (socioeconomic level, 
loneliness, substance abuse)  
 
 
9.4. 
Interim Analysis 
No interim analysis of efficacy will be carried out. Interim analyses of safety variables will  be 
performed throughout the intervention period and monitored by the Data Monitoring Committee. 
 
 
9.5. 
Sample Size Determination 
Approximately 310 participants will be enrolled, randomized and assigned to investigational 
intervention. The sample size calculation is based on the primary efficacy estimand and its endpoint 

 
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SF-36 general health sub score. A difference of 10 points is considered clinically significant (Wyrwick 
2005). The scatter of SF-36 scores among Long COVID sufferers are unknown, but a large Norwegian 
survey reported a Standard Deviation (SD) between 20 and 23 across all age groups (Jacobsen 2017). If 
SD is set to be 25 in the population under study, the study should aim to include a total of 310 
participants. This yields a power of about 90 % (α=0.05) to detect a small to medium effect size, 
allowing up to 20 % lost to follow-up or other protocol deviations.    
 
 

 
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10. 
Supporting Documentation and Operational 
Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
international ethical guidelines 
o Applicable ICH Good Clinical Practice (GCP) guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant documents will 
be submitted to The Norwegian National Research Ethics Committee (REK) by the principal 
investigator and reviewed and approved by the REK before the study is initiated. 
• Any amendments to the protocol will require REK approval before implementation of changes made 
to the study design, except for changes necessary to eliminate an immediate hazard to study 
participants.  
• Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
• The investigator will be responsible for the following, as applicable: 
o Notifying the REK of SAEs or other significant safety findings as required by REK procedures 
o Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies, and all 
other applicable local regulations 
 
10.1.2. 
Financial Disclosure 
This study is financed by governmental funds, thus nothing to disclose. However, each investigator is 
responsible for providing information on personal financial interests during the course of the study and 
for 1 year after completion of the study. 
 
10.1.3. 
Informed Consent Process 
• The investigator or the investigator’s representative will explain the nature of the study, including 
the risks and benefits, to the potential participant and answer all questions regarding the study. 
• Potential participants must be informed that their participation is voluntary. They or their legally 
authorized representatives will be required to sign a statement of informed consent  
• The medical record must include a statement that written informed consent was obtained before the 
participant was enrolled in the study and the date the written consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their participation 
in the study. 
• A copy of the ICF(s) must be provided to the participant. 
 
10.1.4. 
Recruitment strategy 
Recruitment strategy is outlined in paragraph 8.1 

 
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10.1.5. 
Data Protection 
• Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred for statistical analyses will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
• The participant must be informed that their medical records may be examined by authorized 
personnel appointed by appropriate IRB/IEC members and by inspectors from regulatory 
authorities. 
• Information technology systems used to collect, process, and store study-related data are secured by 
technical and organizational security measures designed to protect such data against accidental or 
unlawful loss, alteration, or unauthorized disclosure or access. The present project will utilize the 
Services for Sensitive Data (TSD) at the University of Oslo for all data management 
(https://www.uio.no/english/services/it/research/sensitive-data/index.html). The TSD adheres to the 
most strict requirements for data protection.  
 
10.1.6. 
Committees Structure 
MINIRICO is conducted at Dept. of Paediatrics and Adolscent Health at Akershus University Hospital, 
Norway. Professor/Head of Research Vegard Bruun Bratholm Wyller is Principal Investigator. 
Researcher Maria Pedersen manages the trial on a day-to-day basis. MINRICO is a separate work 
package in the overarching research initiative “Long-term effects of SARS-CoV-2 infection: An 
interdisciplinary observational and interventional study program”, lead by professor Torbjørn Omland. 
There is close collaboration with profs. Silje Endresen Reme and Henrik Børsting Jacobsen at the 
Mind-Body Lab, Dept. of Psychology, University of Oslo. 
The Steering Committee (SC) of MINIRICO consists of Wyller, Pedersen, Omland, Reme and 
Jacobsen, and meets on a quarterly basis. The SC is responsible for all major decisions regarding 
design, management structure, protocol amendments, safety concerns, publication and dissemination 
strategy, etc.  
As described in section 9.4, MINIRICO has employed an independent data monitoring committee 
(IDMC), consisting of three senior academics not otherwise involved in the study. The IDMC will 
receive reports on all AEs/SAEs as well as key variables during the course of the study and may 
recommend unblinding/withdrawal of individual participants and eventual termination the study in case 
of safety concerns. The final decision regarding unblinding/withdrawal and termination is taken by the 
SC. The role and responsibilities of the IDMC is outlined in detail in a separate charter.  
The established Consumer Advisory Group of the Collaborative on Fatigue Following Infections 
(COFFI, www.coffi-collaborative.com) provides regular consumer input on different facets of the 
present project as well.  
10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the designee electronically (eg, laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the CRF. 
• The investigator must permit study-related monitoring, audits, REK review, and regulatory agency 
inspections and provide direct access to source documents. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study will be 
retained by the investigator for 10 years after study completion. No records may be destroyed during 
the retention period without the written approval from the study leaders. No records may be 
transferred to another location or party without written notification to the study leaders. 

 
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10.1.8. 
Source Documents. 
• Source documents provide evidence for the existence of the participant and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF. 
 
10.1.9. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of participants. 
The first act of recruitment is the first telephone conversation between the study center research 
secretary and a potential Long COVID sufferer interested in participation.   
 
10.1.10. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings.  
• The researchers will comply with the requirements for publication of study results.  
• Results will be published in international scientific journals;  publication of negative as well as 
positive results will be pursued.  
• Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 

 
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10.2. 
Appendix 2: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
 
10.2.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
study intervention. 
 
Definition of Unsolicited and Solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary (through Dignio®) and 
that is communicated by a participant/participant’s parent(s) who has signed the informed consent. 
Unsolicited AEs include serious and nonserious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, emergency room visit, or visit to/by a healthcare provider). The 
participants/participant’s parent(s) will be instructed to contact the site as soon as possible to report 
medically attended event(s), as well as any events that, though not medically attended, are of 
participant/participant’s parent(s) concern. Detailed information about reported unsolicited AEs will 
be collected by qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant/participant’s parent(s) will be collected during an interview with the 
participants/participant’s parent(s) and by review of available medical records at the next visit. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, vital signs measurements), including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the investigator (ie, not 
related to progression of underlying disease, or more severe than expected for the participant’s 
condition) 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition 
• New condition detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• Lack of efficacy or failure of expected pharmacological action per se will not be reported as an AE 
or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, 
and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill 
the definition of an AE or SAE. 
 
Events not Meeting the AE Definition 

 
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• Any abnormal laboratory findings or other abnormal safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant’s condition 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen 
 
10.2.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the 
criteria listed: 
 
a. Results in death 
 
b. Is life threatening 
The term life threatening in the definition of serious refers to an event in which the participant was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether hospitalization occurred or was 
necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
 
e. 
Is a congenital anomaly/birth defect 
 
f. 
Is a suspected transmission of any infectious agent via an authorized medicinal product 
 
g. Other situations: 

 
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• Medical or scientific judgment should be exercised by the investigator in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the participant 
or may require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, convulsions not 
resulting in hospitalization, or development of intervention dependency or intervention abuse. 
 
10.2.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE. 
• All AE/SAE will be reported to the steering committee as well as the independent data monitoring 
committee.  
 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to one of the following categories:  
• Mild: A type of adverse event that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily living. 
• Moderate: A type of adverse event that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research participant. 
• Severe: A type of adverse event that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.   
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The investigator will use clinical judgment to determine the 
relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration, will be 
considered and investigated. 
• The investigator must review and provide an assessment of causality for each AE/SAE and 
document this in the medical notes. There may be situations in which an SAE has occurred and the 
investigator has minimal information to include in the initial report. However, it is very important 
that the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data. 

 
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• The investigator may change their opinion of causality in light of follow-up information and send an 
SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated to elucidate the nature and/or causality of the AE or SAE 
as fully as possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the steering committee and the independent data monitoring committee 
with a copy of any postmortem findings including histopathology.  
• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data to the steering committee and the independent 
data monitoring committee within 24 hours of receipt of the information. 
 
10.2.4. 
Reporting of SAEs 
SAE Reporting  
• The primary mechanism for reporting an SAE to the steering committee and the independent data 
monitoring committee and other relevant authorities will be by emails and telephone calls. 
• A designated form for SAE reporting has been developed, containing assessment of causality on a 7-
point Likert scale; for each SAE, this form will be completed by the study physician and attached to 
the notifying emails.   
• All SAEs and related information will be filed at the designated project server area within the TSD.  
 
 
 
 
 

 
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10.3. 
Appendix 3: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located directly 
before the table of contents (TOC). 
 
Amendment #1, 26.01.2023: Minor adjustments of assessment program, inclusion criteria, lifestyle 
restrictions, randomization procedures, therapeutic fidelity assessment, and sample size calculations.  
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
 
Amendment #2, 20.12.20243: Minor adjustments of study rationale, outcome measures, safety 
monitoring routines, compliance assessment, screening procedures, analysis set definition, committee 
structure and SAE reporting; addition of a qualitative substudy.  
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
 

 
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