Fibromyalgia and Naltrexone: The FINAL Study
Phase: PHASE2
Conditions: Fibromyalgia
Sponsor: Odense University Hospital

EudraCT-nr.:  2019-000702-30   Version 5.1     Protocol code: 18.021 
Date:27.07.2021 
 
Page 1 of 34 
 
 
 
 
 
 
 
Clinical Trial Protocol 
 
 
 
 
 
 
Protocol code: 18.021  
Version 5.1 
27.07.2021 
EudraCT-number: 2019-000702-30 
ClinicalTrials.Gov: NCT04270877 
 
 
 
 
 
 
 
 
 
FIbromyalgia and NALtrexone  
 The FINAL study 
 
A randomized, double-blind, placebo-controlled trial 
 

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Table of Contents: 
 
Front page 
 
 
 
 
 
 
1 
Table of Contents 
 
 
 
 
 
2 
 
1. General information 
 
 
 
 
3 
Abbreviations 
 
 
 
 
 
6 
2. Background 
 
 
 
 
 
7 
3. Aim  
 
 
 
 
                     13 
4. Plan for the study  
 
 
 
                     13 
5. Selection and withdrawal of subjects 
 
 
                     18 
6. Treatment of subjects 
 
 
 
                     19 
7. Outcome measures  
 
 
 
                     24 
8. Safety evaluation  
 
 
                                           25 
9. Statistics 
 
 
 
 
                     26 
10. Direct access to sourcedata/sourcedocuments  
 
                     27 
11. Quality control and quality assurance 
 
 
                     27 
12. Ethics 
 
 
 
 
                     27 
13. Handling and filing of data and biological material 
 
                     28 
14. Financing and insurance 
 
 
 
                     29 
15. Publication 
 
 
 
 
                     29 
16. Appendix 
 
 
 
 
                     30 
17. References 
 
 
 
 
                     33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. General information: 
 
The trial will be carried out according to this protocol, ICH-GCP guidelines, national regulatory 
requirements and legislation. The protocol is written following the recommendations given in the 
SPIRIT statement. 
 
Sponsor 
Palle Toft, Professor, MD, PhD, Dr. Med. 
Department of Anesthesiology and Intensive Care 
Odense University Hospital 
Sdr. Boulevard 29 
5000 Odense C 
 
 
____________________________________ 
Email: palle.toft@rsyd.dk  
 
Date 
 
Signature 
 
Primary investigator 
Karin Due Bruun, MD, PhD student 
Pain Research Group, Pain Centre South 
Department of Anesthesiology and Intensive Care 
Odense University Hospital 
Heden 7-9 
5000 Odense C 
 
 
 
Phone: +45 65413869 
 
 
____________________________________ 
Email: karin.due.bruun@rsyd.dk                             Date 
 
Signature 
 
Co investigators 
Kirstine Amris, MD, Dr. Med.  
The Parker Institute & 
Department of Rheumatology 
Bispebjerg and Frederiksberg Hospital, University of Copenhagen 
Nordre Fasanvej 57 
 
 
____________________________________ 
2000 Frederiksberg 
 
 
Date 
 
Signature 
 
 
 
 
Henrik Bjarke Vægter, M.Sc., PhD, post.doc. 
Pain Research Group, Pain Centre South 
Department of Anesthesiology and Intensive Care 
Odense University Hospital 
Heden 7-9 
 
 
 
____________________________________ 
5000 Odense C 
 
 
Date 
 
Signature 
 
Morten Rune Blichfeldt-Eckhardt, MD, PhD, post.doc.  
Pain Research Group, Pain Centre South 
Department of Anesthesiology and Intensive Care 
Odense University Hospital 
Heden 7-9 
 
 
 
____________________________________ 
5000 Odense C 
 
 
Date 
 
Signature 

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Page 4 of 34 
 
 
 
 
 
Anders Holsgaard Larsen, M.Sc., PhD, Associate Professor 
Orthopedic Research Unit, University of Southern Denmark & 
Department of Orthopedics and Traumatology, OUH  
Heden 18 
 
 
 
____________________________________ 
5000 Odense C 
 
 
Date 
 
Signature 
 
 
   
 
Robin Christensen, B.Sc, M.Sc., PhD, Professor of Biostatistics and Clinical Epidemiology 
The Parker Institute 
Bispebjerg and Frederiksberg Hospital, University of Copenhagen 
& Department of Clinical Research, University of Southern Denmark, Odense University Hospital 
 
 
 
 
 
____________________________________ 
 
 
 
 
Date 
 
Signature 
 
GCP-monitoring 
GCP-unit Odense University Hospital 
Department of Clinical Biochemistry and Pharmacology 
J.B. Winsløwsvej 19, 2 
5000 Odense C 
 
Pharmacy 
Hospital Pharmacy Funen 
J.B. Winsløwsvej 13 
5000 Odense C 
 
Glostrup Pharmacy 
Hovedvejen 101 
2600 Glostrup 
 
Data management 
Odense Patient data Explorative Network (OPEN) 
J.B. Winsløwsvej 9A 
5000 Odense C 
 
Place for the trial:  
Pain Research Group, Pain Centre South 
Department of Anesthesiology and Intensive Care 
Odense University Hospital 
Heden 7-9  
5000 Odense C 
 
 
 
 

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Timeframe 
 
Approval from authorities:  
 
30.10.2019 
Expected start of inclusion:  
 
01.11.2020 
Expected end of inclusion:  
 
01.01.2023 
Expected end of follow-up :  
 
01.06.2023 
Expected submission of papers: 
 
01.01.2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abbreviations: 
FM 
= 
Fibromyalgia 
CSF 
= 
Cerebrospinal Fluid 
ADL 
= 
Activities of Daily Living 
NLX 
=  
Naltrexone 
LDN 
= 
Low Dose Naltrexone 
MS 
= 
Multiple sclerosis 
TLR4 
= 
Toll-Like Receptor 4 
Mg 
= 
Milligram 
VAS 
= 
Visual analog scale 
NRS 
= 
Numeric Rating Scale 
RCT 
= 
Randomized Clinical Trial 
SmPC 
= 
Summary of product characteristics 
ED50 
= 
Effective dose in 50% 
ED95 
= 
Effective dose in 95% 
ACR1990 
= 
American College of Rheumatology 1990 classification criteria 
FIQR 
= 
Revised Fibromyalgia Impact Questionnaire 
PGI-I 
= 
Patient Global Impression of Improvement 
VRS 
= 
Verbal Rating Scale  
EQ-5D 
= 
EuroQol – 5 dimentions 
EQ-VAS 
= 
EuroQol – visual analog scale 
ACR-2016 = 
The American College of Rheumatology 2016 revised criteria for FM 
EMG 
= 
Electromyography  
CPM 
= 
Conditioned pain modulation  
TSP 
= 
Temporal summation of pain  
CRP 
= 
C-reactive protein 
ALAT 
= 
Alanine-aminotransferase 
GFR 
= 
Glomerular-filtration-rate 
hCG 
= 
Human chorionic gonadotropin 
ECG 
= 
Electrocardiogram 
PHQ-9 
= 
Patient Health Questionnaire – 9 item  
GAD-7 
= 
Generalized Anxiety Disorder – 7 item 
MCID 
= 
Minimal clinical important difference 
PI 
= 
Primary Investigator 
ID 
= 
Identity number 
E-CRF 
= 
Electronic case report form 
AE 
= 
Adverse Events  
AR 
= 
Adverse Reactions 
NSAID 
= 
Non Steroidal Anti-inflammatory Drug  
SAE 
= 
Serious Adverse Events  
SAR 
= 
Serious Adverse Reactions  
SUSAR 
= 
Serious Unexpected Suspected Adverse Reactions 
VAS 
= 
Visual analogue scale 
Hz 
= 
Hertz 
RMS 
= 
Root mean square  
MPF 
= 
Amplitude and median power frequency 
SMS 
= 
Short Message Service 

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2. Background 
2.1 Background for the trial 
Fibromyalgia (FM) is a condition characterized by chronic widespread pain and tenderness 
accompanied by symptoms like fatigue, sleep disturbances, cognitive disturbances, dysregulation of 
the autonomic nervous system, increased sensitivity to other sensory inputs, anxiety, depression etc. 
[1]. FM is a common disorder affecting approximately 2% of the general population [2]. Most often 
no pathology can be found in the tissue that can explain the pain, and evidence points to the fact 
that FM is caused by disturbances in central pain regulatory mechanisms [3, 4]. FM patients have 
been shown to have increased levels of enkephalins in the cerebrospinal fluid (CSF) [5] and 
decreased mu receptor availability has been demonstrated [6], suggesting that these patients also 
have a dysfunction in endogenous analgesia.  
A key finding in patients with FM is widespread hyperalgesia to mechanical 
stimulation [7] and low pain thresholds for both mechanical and thermal stimulation [8, 9]. This can 
explain why FM patients have characteristic complaints of not only generalized pain but also 
generalized tenderness. Another predominant feature in FM is early muscular fatigue and 
intolerance to physical activity [10, 11], which can contribute to a debilitating decreased ability to 
perform activities of daily living (ADL). A previous study investigating muscular exhaustion in FM 
patients, have revealed a low correlation between perceived exhaustion and objective signs of 
muscle fatigue measured by electromyography, suggesting that also this symptom can be related to 
dysfunction in central regulatory mechanisms [12]. 
Naltrexone (NLX) has opioid receptor antagonistic effect [13], and it has been known 
for decades that NLX can have “paradoxical analgesic effect” when used in low doses [14]. In 
recent years low dose naltrexone (LDN) has been used widely as off-label treatment for pain and 
inflammation in multiple sclerosis (MS), Crohn’s disease and fibromyalgia (FM) [15]. In Norway 
0.3% of the general population has been shown to use LDN [16], the evidence is however sparse. 
The mechanisms of action of LDN are not fully understood, but could be regulation of homeostasis 
in the endorphin system, leading to enhanced endogenous analgesia and/or an anti-inflammatory 
effect mediated via blockade of toll-like receptor 4 (TLR4) leading to attenuation of central 
sensitization.  
 
The proposed mechanisms of action of LDN are:  
1) Opioid Antagonism 
In animal models chronic administration of naltrexone has been shown to increase expression of 
preproenkephalin mRNA 12-fold, leading to increased levels of enkephalins and increased 
density of opioid receptors in the brain [17]. This is thought to enhance endogenous analgesia 
[18]. 
2) Toll-like Receptor 4 (TLR4) blockade in astrocytes and glia cells 
In response to pain, astrocytes and microglia cells can initiate a proinflammatory cytokine 
cascade, thought to be involved in the development and maintenance of chronic pain [19]. LDN 
blocks TLR4 and human studies have demonstrated  that LDN reduces the level of 
proinflammatory cytokines in FM patients [20]. Targeting TLR4 is a new emerging therapeutic 
field that holds promise as disease-modifying and opioid-sparing alternatives for persistent pain 
states [21] 
 
Since no specific pharmacological treatments of FM is available, the existing pharmacological 
agents aims at either reducing facilitatory neurotransmitters (e.g. gabapentinoids), or increasing 
inhibitory neurotransmitters (e.g. Serotonin Norepinephrine Reuptake Inhibitors) [22]. LDN might 

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be a new disease modifying therapy that could potentially reduce neuroinflammation and induce 
homeostasis in the endorphin system in FM patients.  
 
2.2 Summary of results from previous LDN-related clinical trials 
Only 2 small placebo-controlled studies have investigated the effect of LDN on FM.  
The first study was a single blind, observational prospective cohort study with participation of only 
10 women with FM [23]. The participants received placebo for 2 weeks, followed by 8 weeks 
treatment with LDN 4.5 mg. The primary endpoint was self-reported overall fibromyalgia 
symptoms during the last 24 hours, on a 0-100 visual analog scale (VAS). FM symptoms were 
averagely reduced by 32.5% during treatment with LDN, and 2.3% during placebo treatment. Sixty 
percent (6/10) were classified as responders, having more than a 30% reduction of their FM 
symptoms. 
The same research team later carried out a small placebo controlled randomized 
clinical trial (RCT) with participation of 31 women with FM [24]. It was designed as a crossover 
study, and participants were randomized to either 4 weeks of placebo followed by 12 weeks of 
treatment with LDN 4.5 mg, or 12 weeks of treatment with LDN 4.5 mg followed by 4 weeks of 
placebo. Primary endpoint was average pain during the last 3 days rated on a 0-100 VAS. The 
average reduction of pain was 28.8% when treated with LDN and 18% when treated with placebo. 
The between-group difference was significant (P = 0,016).Thirty-two percent of the subjects 
receiving LDN were classified as responders, defined as having a minimum 30% reduction of pain 
plus a minimum of 30% improvement of fatigue or sleep. In the placebo group the response rate 
was 11%. The differences in response rates were significant. 
 
2.3 Background information about Naltrexone 
NLX is marketed as an additional therapy for supporting abstinence in patients with previous abuse 
of opioids or alcohol, and doses of 50 mg/day is traditionally used [25]. NLX is primarily known 
for its antagonistic effect on the opioid receptor [13], but is also thought to blunt dopaminergic 
transmission in mesolimbic pathways, thereby attenuating craving and reinforcing effects of alcohol 
[26]. NLX has the same biochemical structure as Naloxone, but has a higher oral bioavailability and 
a longer half-life [27].  
 
2.4 Known and potential side effects, risks and possible benefits for the subjects 
Risks: 
In several clinical studies LDN has been shown to be well tolerated when used for treatment of FM, 
MS or Crohns disease [15]. No serious adverse events have been reported in any of the clinical 
studies of LDN. Possible side effects of Naltrexone 50 mg is listed in the Summary of Product 
Characteristics (SmPC) below. In this study a dose of 6 mg is used, and the risk of serious adverse 
events when using this low dose is considered to be minimal. 
 
Benefits: 
Potential benefits for the participants are that they might experience reduced tenderness, reduced 
pain, improved sleep, improved energy and improvement in daily functioning. All participants will 
be offered treatment with LDN in an individual dosing after termination of the trial. The results 
from the study will be of benefit for other patients with FM.  
 
SmPC for Naltrexone 50 mg: 

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The following undesirable effects are ranked according to system organ class and to their 
frequency: 
Very common (≥ 1/10) 
Common (≥1/100 to < 1/10) 
Uncommon (≥1/1,000 to < 1/100) 
Rare (≥ 1/10,000 to < 1/1,000) 
Very rare (< 1/10,000) 
not known (cannot be estimated from the available data) 
MedDRA system organ class  
 
Infections and infestation  
 
Uncommon  
Oral herpes  
 
Tinea pedis  
Blood and lymphatic system disorders  
 
Uncommon  
Lymphadenopathy  
Rare  
Idiopathic thrombocytopenic purpura  
Metabolism and nutrition disorders  
 
Common  
Decreased appetite  
Psychiatric disorders:  
 
Very common  
Nervousness  
 
Anxiety  
 
Insomnia  
Common  
Affective disorders  
 
Despondency  
 
Irritability  
 
Mood swings  
Uncommon  
Hallucination  
 
Confusional state  
 
Depression  
 
Paranoia  
 
Disorientation  
 
Nightmare  
 
Agitation  
 
Libido disorder  
 
Abnormal dreams  
Rare  
Suicidal ideation  

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Attempted suicide  
Very rare  
Euphoria  
Nervous system disorder  
 
Very common  
Headache  
 
Sleep disorders  
 
Restlessness  
Common  
Dizziness  
 
Shivering  
 
Vertigo  
Uncommon  
Tremor  
 
Somnolence  
Rare  
Speech disorder  
Eye disorders  
 
Common  
Lacrimation increased  
Uncommon  
Vision-blurred  
Eye irritation  
 
Photophobia  
 
Eye swelling  
 
Eye pain  
 
Asthenopia  
Ear and labyrinth disorders  
 
Uncommon  
Ear discomfort  
 
Ear pain  
 
Tinnitus  
 
Vertigo  
Cardiac disorders  
 
Common  
Tachycardia  
 
Palpitations  
 
Electrocardiogram change  
Vascular disorders  
 
Uncommon  
Blood pressure fluctuation  
 
Flushing  
Respiratory, thoracic and mediastinal disorder  
 
Common  
Chest pain  
Uncommon  
Nasal congestion  
 
Nasal discomfort  
 
Rhinorrhea  

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Sneezing  
 
Oropharyngeal pain  
 
Sputum increased  
 
Sinus disorder  
 
Dyspnoea  
 
Dysphonia  
 
Cough  
 
Yawning  
Gastrointestinal disorder  
 
Very common  
Abdominal pain  
 
Abdominal cramps  
 
Nausea or Inclination to vomit  
 
Vomiting  
Common  
Diarrhoea  
 
Constipation  
Uncommon  
Flatulence  
 
Haemorrhoids  
 
Ulcer  
 
Dry mouth  
Hepatobiliary disorders  
 
Uncommon  
Liver disorder  
 
Blood bilirubin increased  
 
Hepatitis  
 
During treatment an increase of liver 
transaminases may occur. After 
discontinuation of Naltrexone the 
transaminases decreased to baseline 
within several weeks.  
Skin and subcutaneous tissue disorder  
 
Common  
Rash  
Uncommon  
Seborrhoea  
 
Pruritus  
 
Acne  
 
Alopecia  
Very rare  
Exanthema  
Musculoskeletal and connective tissue disorders :  
 
Very common  
Arthralgia  

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Myalgia  
Uncommon  
Groin pain  
Very Rare  
Rhabdomyolysis  
Renal and urinary disorders  
 
Common  
Urine retention  
Uncommon  
Pollakiuria  
 
Dysuria  
Reproductive system and breast disorders  
 
Common  
Delayed ejaculation  
 
Erectile dysfunction  
General disorder and administration site conditions  
 
Very common  
Feebleness  
 
Asthenia  
Common  
Lack of appetite  
 
Thirst  
 
Energy increased  
 
Chills  
 
Hyperhidrosis  
Uncommon  
Increased appetite  
 
Weight loss  
 
Weight gain  
 
Pyrexia  
 
Pain  
 
Peripheral coldness  
 
Feeling hot  
 
 
2.5 Description and justification of dose, dosing regimen and treatment period. 
In previous clinical trials one daily dose of 4.5 mg LDN has been tested. One daily dosing will lead 
to an intermittent blockade of mu receptors, and it has been suggested that this intermittent 
blockade is important for LDN to exert its regulation of the homeostasis in the endorphin system in 
the brain.  
To be able to choose a dose that is both sufficiently effective and tolerable in as many 
patients as possible, our research group has conducted a dose-response study prior to this study 
(paper in press). Subjects included in the study were women aged 18-60 with a diagnose of FM. In 
the dose-response study we found that 3.88 mg was the dose effective in 50% (ED50) and 5.4 mg 
was the dose effective in 95% (ED95). In the dose-response study, doses higher than 6 mg was not 
tested and we did not find problems with safety or tolerability using doses up to 6 mg. Based on 
these findings we conclude that 6 mg is an appropriate test dose.   

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From previous clinical trials it has been shown that pain is reduced with more than 30% in 57-60% 
of FM patients after 8-12 weeks of treatment with LDN [24]. In a clinical trial investigating 
immune effects of LDN, proinflammatory cytokines was significantly reduced after 8 weeks of 
treatment with LDN [20]. 
Thus, based on results from previous clinical trials, we have chosen the treatment 
period in this study to be 12 weeks including a titration phase of 4 weeks (i.e. 4 first weeks of the 12 
week period).  
 
2.6 Description of the study population 
The study population will consist of female participants (age 18-64 years), who fulfills the 
classification criteria for FM according to the American College of  Rheumatology 1990 
(ACR1990) [7].  
 
3. Aim of the study 
3.1 Hypothesis: 
LDN treatment will be superior in reducing pain in FM patients compared with placebo. 
 
3.2 Aims and objectives: 
The aim of the trial is to investigate whether treatment with LDN has a superior effect compared to 
placebo on pain among female patients with fibromyalgia, evaluated after 12 weeks of treatment. In 
the study we will also explore secondary aims regarding a possible improvement of other FM core 
symptoms.  
Our primary efficacy objective will be to compare the effect of drug LDN, relative to 
placebo, on changes in average pain during the last 7 days, from baseline to week 12, in female 
patients with fibromyalgia. 
Our key secondary efficacy objectives will be to compare the effect of drug LDN, 
relative to placebo, on  (i) global assessment and on (ii) changes in pain, (iii) tenderness, (iv) 
fatigue, (v) sleep disturbance, (vi) depression, (vii) anxiety, (viii) cognition, (ix) stiffness, (x) 
physical function, (xi) quality of life and (xii) pain distribution from baseline to week 4, 8 and 12, in 
female patients with fibromyalgia. Furthermore, responder indices will be compared between the 
treatment groups.  
Among the exploratory secondary objectives are changes in muscle exhaustion, 
physical fitness, pain sensitivity, inhibition of pain, augmentation of pain, and pro-inflammatory 
cytokines. 
 
4. Plan for the study 
4.1 Primary and secondary end-points 
Primary end-point:  
 Average pain during the last 7 days. Change from baseline when assessed after 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Assessed by asking the 
participants about the level of average pain during the last 7 days on a 11 point rating scale 
(ranging from “no pain” to “unbearable pain”) using the first item from the symptom part of 
the Fibromyalgia Impact Questionnaire Revised (FIQR) [28] 
 
Key Secondary end-points:  

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 Global assessment. Change in overall fibromyalgia symptoms from baseline when 
assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo (between-
group difference). Measured by Patient Global Impression of Change (PGI-C) on a 1-7 
Verbal Rating Scale (VRS). The participants are asked how they rate their overall 
fibromyalgia symptoms after 4, 8 and 12 weeks of treatment compared with before 
treatment. A score of 4 indicates “no change”, a score of 1 is characterized by “a lot 
worse” and a score of 7 is characterized by “a lot better”. 
 Impact of fibromyalgia. Change from baseline when assessed after 4, 8, and 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Measured by the 
FIQR total score. The FIQR asks patients to rate how difficult it is to perform a list of 9 
common activities over the previous 7 days on an 11 point scale (ranging from "no 
difficulty" to "very difficult"). The FIQR then asks patients to indicate how often their 
fibromyalgia impacts their quality of life over the last 7 days on an 11 point scale 
(ranging from "never" to "always"). Finally, the FIQR asks patients to assess the severity 
of 10 different symptoms on an 11 point scale (ranging from no symptoms to extreme 
symptoms). These three sub-scales are summed to represent an overall FIQR score. A 
lower score indicates lower severity. 
 Health-related quality of life. Change from baseline when assessed after 4, 8, and 12 
weeks of treatment with LDN or LDN-placebo (between-group difference). Measured 
by EuroQol-5D (EQ-5D) and EuroQol-VAS (EQ-VAS) [29]. The EQ-5D measures 5 
domains 
including 
mobility, 
self-care, 
usual 
activities, 
pain/discomfort 
and 
anxiety/depression. Every domain is rated on a 1-5 VRS, a score of 1 indicating no 
problems, and a score of 5 indicating extreme problems. The EQ-VAS asks the 
participant to rate their overall health ‘today’ on a 0-100 VAS.  
 Pain distribution. Change from baseline when assessed after 4, 8, and 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Assessed by the 
Widespread Pain Index (WPI) from The American College of Rheumatology 2016 
revised criteria for FM (ACR-2016) [30]. The body is divided into 19 body parts and 
number of pain full body parts during the last 7 days is counted, giving rise to the WPI.  
 Level of pain. Change from baseline when assessed after 4, 8, and 12 weeks of treatment 
with LDN or LDN-placebo (between-group difference. Assessed by the FIQR “level of 
pain” question, asking the participants to rate the average level of pain during the last 7 
days on a 11 point rating scale (ranging from “no pain” to “unbearable pain”) 
 Level of tenderness. Change from baseline when assessed after 4, 8, and 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Assessed by the FIQR 
“level of tenderness to touch” question, asking the participants to rate the average level 
of tenderness to touch during the last 7 days on an 11 point rating scale (ranging from 
“no tenderness” to “very tender”).  
 Pain threshold. Change from baseline when assessed after 12 weeks of treatment with 
LDN or LDN-placebo. Assessed using a handheld algometer. Points measured: Right 
Quadriceps 15 cm proximal of apex patella and left Trapezius 10 cm from acromion. 
Each point is measured 3 times.  
 Level of fatigue. Change from baseline when assessed after 4, 8, and 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Assessed by the FIQR 
“level of energy” question, asking the participants to rate the average level of energy 

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during the last 7 days on an 11 point rating scale (ranging from “lots of energy” to “no 
energy”). 
 Level of Sleep disturbance. Change from baseline when assessed after 4, 8, and 12 
weeks of treatment with LDN or LDN-placebo (between-group difference). Assessed by 
the FIQR “quality of sleep” question asking the participants to rate the average quality 
of sleep during the last 7 days on an 11 point rating scale (ranging from “awoke well 
rested” to “awoke very tired”).  
 Level of depression. Change from baseline when assessed after 4, 8, and 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Assessed by the FIQR 
”level of depression” question, asking the participants to rate the average level of 
depression during the last 7 days on an 11 point rating scale (ranging from “no 
depression” to “very depressed”). 
 Level of anxiety. Change from baseline when assessed after 4, 8, and 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Assessed by the FIQR 
“level of anxiety” question, asking the participants to rate the average level of anxiety 
during the last 7 days on an 11 point rating scale (ranging from “not anxious” to “very 
anxious”). 
 Level of Cognition. Change from baseline when assessed after 4, 8, and 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Assessed by the FIQR 
“level of memory problems” question, asking the participants to rate the average level of 
memory problems during the last 7 days on an 11 point rating scale (ranging from “good 
memory” to “very poor memory”). 
 Level of Stiffness. Change from baseline when assessed after 4, 8, and 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Assessed by the FIQR 
“level of stiffness” question, asking the participants to rate the average level of stiffness 
during the last 7 days on an 11 point rating scale (ranging from “no stiffness” to “severe 
stiffness”) 
 Level of Physical function. Change from baseline when assessed after 4, 8, and 12 
weeks of treatment with LDN or LDN-placebo (between-group difference). Assessed by 
the physical function domain of FIQR; asking patients to rate how difficult it is to 
perform a list of 9 common activities over the previous 7 days on an 11 point scale 
(ranging from "no difficulty" to "very difficult"). The score is characterized by the sum 
of the 9 scores (0-90), a lower score indicates better function. 
 Number of responders with a more than 15% improvement of the primary outcome. 
(Number of responders are calculated for both the LDN and the LDN-placebo group)  
 Number of responders with a more than 30% improvement of the primary outcome. 
(Number of responders are calculated for both the LDN and the LDN-placebo group) 
 Number of responders with a more than 50% improvement of the primary outcome. 
(Number of responders are calculated for both the LDN and the LDN-placebo group) 
Exploratory secondary end-points:  
 Variation in pain. Change from baseline when assessed after 8, and 12 weeks of 
treatment with LDN or LDN-placebo (between-group difference). Measured using a 
diary of daily average pain rated on an 11 point rating scale during 7 days before visits at 
baseline, and after 8 and 12 weeks of treatment. The variation in pain is characterized by 
the highest score minus the lowest score during the 7 days.  

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 Muscle exhaustion. Change from baseline when assessed after 12 weeks of treatment 
with LDN or LDN-placebo (between-group difference). Measured by an isometric 
muscle exhaustion test of the deltoid muscle as described under section 6.3. in this 
protocol. 
 Physical fitness. Change from baseline when assessed after 12 weeks of treatment with 
LDN or LDN-placebo (between-group difference). Measured by the 30-second chair 
stand test as described under section 6.3 in this protocol. 
 Pain sensitivity. Change from baseline when assessed after 12 weeks of treatment with 
LDN or LDN-placebo (between-group difference). Measured by cuff-algometry as 
described under the section 6.3 in this protocol. 
 Inhibition of pain. Change from baseline when assessed after 12 weeks of treatment with 
LDN or LDN-placebo (between-group difference). Measured by Conditioned pain 
modulation (CPM) as described under section 6.3 in this protocol. 
 Augmentation of pain. Change from baseline when assessed after 12 weeks of treatment 
with LDN or LDN-placebo (between-group difference). Measured by Temporal 
Summation of Pain (TSP) as described under section 6.3 in this protocol 
 Inflammation. Change in level of cytokines from baseline when assessed after 12 weeks 
of treatment with LDN or LDN-placebo (between-group difference). Measurement of 
levels of pro-inflammatory cytokines in plasma or serum is carried out.  
 
Data collected at baseline:  
 Demographic data 
 Concomitant medicine 
 Serum levels of C-reactive protein (CRP), bilirubin, Alanine-aminotransefase (ALAT), 
creatinine, Glomerular-filtration-rate (GFR), thrombocyte count 
 Electrocardiogram (ECG)  
 Vital signs (Blood pressure, weight, height) 
 Urine – Human chorionic gonadotropin (hCG) 
 Patient Health Questionnaire – 9 item (PHQ-9) [31] 
 Generalized Anxiety Disorder – 7 item (GAD-7) [32] 
 
 
4.2 Description of study design 
The study is designed as a parallel randomized (1:1) double blind, placebo-controlled superiority 
trial.  
 
4.3 Sample size and power calculation 
We used values from our previous dose-response study, and determined that the self-reported pain 
on a 0-10 NRS at baseline had a mean of 6.7 with a standard deviation of 1.5 NSR units. According 
to IMMPACT guidelines a minimal clinical important difference (MCID) is defined as a 15% 
decrease in pain. An improvement of the patients’ condition corresponding to a 15% decrease on 
average in pain is equivalent in the present patient group to a reduction of 1.0 on a 0-10 NRS [33]. 
With a power of 0.80 and a significance level of 0.05 we will need 74 patients, 37 patients in each 
group, to demonstrate a between-group difference equivalent to at least 15% improvement on the 
between-group change score (i.e. a difference between groups of 1.0 NRS units). Expecting some 
attrition and drop-out for the  12 weeks trial period  it was decided to include 100 patients, in the 
total intention-to-treat (ITT) population (50:50), corresponding to a statistical power of more than 

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90% anticipating that they all remain in the ITT population. Thus 100 patients will be randomized 
to treatment with LDN or placebo for 12 weeks, with 50 participants in each arm. 
  
4.4 Measures for reduction of bias 
The RCT study is triple blinded, meaning that participating patients, investigators, outcome 
assessors and statistical analysts are all blinded regarding the allocation. After baseline all 
questionnaire data will be filled in by the patient via an electronic survey prior to the visits. An 
independent assessor will perform all protocol specific procedures after baseline. Unblinding will 
first take place after primary analysis of the data has taken place. 
 A data manager, otherwise not involved in the study, will create a randomization list, 
using a computerized algorithm. The randomization list will be sent to the Hospital Pharmacy 
Funen, who will label the medicine with blinding codes according to this list. The active medicine 
and placebo tablets will look similar and will be blinded in similar cans. The medicine will be 
shipped to the place of the trial together with individual code-envelopes for every blinding code. A 
copy of the randomization list will be stored behind double lock at the office of the sponsor.  
In case of a SUSAR the participating patients will be unblinded by sponsor before 
reporting to the Danish Medicines Agency. Primary investigator (PI) remains blinded. 
Primary investigator is only unblinded in case of a medical emergency, and only if PI finds it 
necessary to ensure the safety of the subject. PI can unblind a single subject by breaking the code-
envelope related to the subjects blinding code. The code-envelopes will be stored together with the 
trial medication at the site of the trial and can be accessed 24/7. In case of unblinding of Primary 
investigator this is documented in the patients file. If a code-envelope is opened, it is stored in the 
trial master file. 
 
4.5 Description of the treatment in the study 
After inclusion the participants are randomized according to the abovementioned procedure to 
receive either placebo or LDN for 12 weeks. Participants will be titrated up to 6 mg following a 
dose escalation scheme: Initial dosage of 1.5 mg daily, escalated every seventh day by 1.5 mg up to 
6 mg at week 4. Dose escalation will be based on safety and tolerability, and if dose escalation is 
not feasible, delayed increments are allowed. After end of titration (week 4) the subjects will be 
maintained at 6 mg or the highest tolerated dose level for the last 8 weeks of the treatment period.  
The active LDN-medicine and LDN-placebo is manufactured at Glostrup Pharmacy 
and shipped to Hospital Pharmacy Funen, where it is canned and labeled. The trial medicine will be 
labeled with blinding codes according to the randomization list by Hospital Pharmacy Funen. 
Before handing out the trial medication, the ID-number of the subject will be written on the 
medicine cans. The trial medicine is taken once daily in the evening, between 7 pm and 11 pm.  
 
4.6 Description of expected timeframe for the individual participant 
The timeframe for the study is 16 weeks. This includes a 12 week intervention period (week 0 to 
12) and a 4 week follow-up period (week 12 to 16). 
 
4.7 Rules for termination the study 
The participants will be withdrawn from the study in case of:  
- 
Serious adverse reactions 
- 
If the subject wants to withdraw 
- 
If changes in the participants other pain medication occur during the trial 
 

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However, we will attempt to contact all patients corresponding to closure of the trial, since no 
statistical approaches for imputation of missing data can compete with the real patient data. 
 
If the intended sample size is not reached at 30 months after recruitment has started, the 
inclusion of patients will stop at 74 patients, which will ensure a power of 80%. 
 
 
4.8 Procedures for accounting for the trial medicine, including placebo products  
The study medicine and the placebo tablets are prepared at Glostrup Pharmacy. The study 
medication is shipped from Glostrup Pharmacy to the Hospital Pharmacy Funen, where it is canned 
and labeled. Hospital Pharmacy Funen will provide the medicine cans with a blinding code 
according to the randomization list. The study medicine will be delivered together with code-
envelopes from the Hospital Pharmacy Funen to the place of the trial (Pain Centre South), where 
the medicine is stored in a locked medicine deposit room. The medicine is stored in a separate shelf, 
clearly separated from other medicine. When the study medication is received, a receipt is made as 
recommended by the GCP unit. A copy of the randomization list is stored by Sponsor behind 
double lock. The individual code-envelopes are stored together with the trial medication. 
Participants included in the study will receive an ID-number and the subjects will be 
randomized to placebo or active treatment. Both ID-number and blinding code is documented in the 
patient medical file. The ID-number is written on the medicine cans at the site of the trial. 
The participants are treated with active medicine or placebo for 12 weeks. Trial 
medication is handed out at baseline (week 0). The first 4 weeks of treatment the dose is titrated up, 
starting with 1.5 mg and increasing the dose with 1.5 mg every seventh day up to 6 mg. At the visits 
during the intervention phase, empty medicine-cans for the previous period will be returned and any 
non-ingested medicine will be counted. Participants will be asked at every visit if they lost any of 
the tablets. Both number of returned tablets and number of lost tablets will be documented.  
 
4.9 Source data 
Source data that appears from the electronic case report form (E-CRF) are demographic data, 
questionnaire data, adverse events (AE) and adverse reactions (AR) and data from protocol specific 
procedures: Pain threshold, pain sensitivity, CPM, TSP and 30-second chair stand test.  
Source data from the isometric muscle exhaustion test will be stored in a secure Sharepoint. 
Source data that appears from the subjects file are data about concomitant medicine and laboratory 
data (blood tests and ECG).  
 
5. Selection and withdrawal of participants 
5.1 Selection and screening of subjects 
Patients are recruited from a pain clinic at Odense University Hospital and through advertising in 
relevant written and internet media. Participants recruited from the pain clinic will receive written 
information from their physician or nurse. Participants that respond through advertisement will 
receive written information material by e-mail about the trial. All participants will afterwards 
receive a telephone call where oral information will be given. Participants that are interested in 
participating will be seen at a screening interview to establish whether they fulfill the in- and 
exclusion criteria. Written informed consent is given at the beginning of the screening interview.  
 
5.2 Inclusion criteria 
The following inclusion criteria are applied: 

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- 
Women aged 18-64 years 
- 
Understands and writes Danish 
- 
Fulfills the ACR1990 criteria for FM 
- 
A minimum score of 4 in self-reported average pain during the last 7 days on a 0-10 NRS at 
baseline 
- 
All fertile women have to use safe anti conception (Spiral, birth control pills, contraceptive 
patch, contraceptive vaginal ring or gestagen injections) for 3 weeks before and 1 week after 
the trial. If the participants’ normal lifestyle includes sexual abstinence, they do not have to 
use anti conception. Instead they can give an oral informed consent, that they will be 
sexually abstinent during the trial. A woman is considered non-fertile if she is sterilized, 
hysterectomized, bilateral oophorectomized or is postmenopausal. A woman is considered 
postmenopausal when vaginal bleeding has been absent for 1 year and is confirmed by 
measurement of follicle-stimulating hormone. 
 
5.3 Exclusion criteria 
The following exclusion criteria are applied:  
- 
Known allergy against naltrexonehydroclorid 
- 
Pregnancy or breastfeeding. A negative pregnancy test has to be available for all fertile 
subjects at baseline 
- 
Use of opioids or NSAIDs up to 4 weeks before inclusion in the trial 
- 
Known abuse of alcohol or other substances 
- 
Known inflammatory rheumatic diseases 
- 
Known demyelinating diseases 
- 
Known active cancer   
- 
Liver dysfunction (ALAT must not be elevated more than 2-fold over highest reference 
level) 
- 
Kidney dysfunction (GFR < 59 mL/min) 
- 
Psychotic diseases 
- 
History of suicide attempts 
- 
Suicide ideation – evaluated using PHQ-9 (Item 9 has to be answered “never”) 
 
5.4 Procedures for withdrawal  
A participant will be withdrawn from the study:  
1) In case of SAR. Participants will be instructed to cease the treatment immediately if a SAR 
is suspected. Follow-up is made regularly until the symptoms are resolved or stable.  
2) In case of non-compliance. The participants will receive the trial medicine for 12 weeks. 
Trial medicine is handed out for 4 weeks at a time. Visits are performed at screening, at 
baseline (week 0), after 2, 4, 8, 12 weeks of treatment and 4 weeks after end of trial. The 
visit at week 2 is a telephone visit. Empty medicine-cans are returned at follow-up visits. 
Medicine that has not been ingested is counted and any loss of medicine is reported. The 
participant is considered non-compliant if adherence to the medication is less than 80%. 
3) If major changes to the participants concomitant pain medication is needed during the 12 
weeks of treatment. At every visit the patients shared medication record is updated. If any 
change in dosing of current pain medication or any new pain medication is registered, the 
participant is withdrawn from the study.  
4) If the participant wants to withdraw. If the participant at any time during the trials wants to 
cease the treatment, the participant is withdrawn from the study. 

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All participants that are withdrawn from the study will be encouraged to complete all visits as 
scheduled. Participants that are withdrawn will not be replaced. According to our sample size 
calculation, we will include participants enough to tolerate a drop-out rate of up to 25%. Data will 
be collected from participants that are withdrawn and relevant data will be analyzed. Both intention 
to treat and per protocol analysis will be performed and compared to assess the robustness of the 
primary analyses. 
 
6. Treatment of participants 
6.1 Description of the treatment 
The participants will receive trial medication in a total of 12 weeks. The medicine is ingested once 
daily in the evening between 7 PM and 11 PM. The participants are randomized to receive either 
active treatment with 6 mg LDN or placebo. After termination of the study, the participants are 
offered treatment with LDN in an individualized dosing.  
 
Screening visit (week -4 to 0):  
- 
Informed consent 
- 
ECG 
- 
Blood testing 
- 
Urine-hCG  
- 
Physical examination 
- 
Medical history 
- 
Medication history 
- 
Demographic data 
- 
PHQ-9 and GAD-7 
- 
Adverse events 
- 
Subjects are assessed if they meet the in- and exclusion criteria 
 
Randomization (week 0):  
- 
Medication history 
- 
PROMs 
- 
Vital signs 
- 
Urine-hCG 
- 
Adverse events 
- 
Algometry 
- 
Cuff-algometry 
- 
CPM/TSP 
- 
30-second chair stand test 
- 
Muscle exhaustion test  
- 
Randomization to LDN or placebo 
- 
Hand out of medicine for the titration phase weeks 1-4, treatment phase weeks 5-8 and 
treatment phase weeks 9-12 in three separate cans. 
 
Telephone visit – titration phase (week 2 +/- 2 days) 
- 
Adverse events 
- 
Compliance assessment 
 

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End of titration - telephone (week 4 +/- 2 days)  
- 
Medication history 
- 
PROMs 
- 
Urine-hCG (measured at home) 
- 
Adverse events  
 
Follow up visit – telephone (week 8 +/- 7 days): Medication history 
- 
Medication history 
- 
PROMs 
- 
Urine-hCG (measured at home) 
- 
Adverse events  
 
End of trial (week 12 +/- 7 days):  
- 
Return of empty medicine cans 
- 
Assessment of compliance 
- 
Medication history 
- 
PROMs 
- 
Vital signs 
- 
Urine-hCG 
- 
Adverse events 
- 
Algometry 
- 
Cuff-algometry 
- 
CPM/TSP 
- 
30-second chair stand test 
- 
Muscle exhaustion test  
- 
ECG 
- 
Blood testing 
 
End of follow-up visit - telephone (week 16 +/- 7 days):  
- 
Medication history 
- 
PROMs 
- 
Adverse events 
 
6.2 Visit schedule 
 
Study phase 
Screening 
Intervention 
End of 
follow-up 
 
 
Randomization 
Up-titration 
Follow-up 
End of trial 
 
Week 
-4 to 0 
0 
2* 
 +/- 2 days 
4* 
+/- 2 days 
8* 
+/- 7 days 
12 
+/- 7 days 
16* 
+/- 7 days 
Eligibility 
screening 
 
x 
 
 
 
 
 
 
Informed 
consent 
 
x 
 
 
 
 
 
 
Physical 
examination 
 
x 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
PHQ-9 and 
GAD-7 
 
x 
 
 
 
 
 
 

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Medication 
history 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Blood testing  
x 
 
 
 
 
x 
 
ECG 
x 
 
 
 
 
x 
 
Vital signs 
 
x 
 
 
 
x 
 
Urine-hCG 
x 
x 
 
x** 
x** 
x 
 
PROMs 
 
x 
 
x 
x 
x 
x 
Computerized 
cuff algometry 
 
x 
 
 
 
x 
 
Handheld 
pressure 
algometry 
 
x 
 
 
 
x 
 
CPM/TSP 
 
x 
 
 
 
x 
 
Muscle 
exhaustion test 
 
 
x 
 
 
 
 
 
x 
 
30s stand chair 
test 
 
 
x 
 
 
 
 
 
x 
 
Medicine 
allocation 
 
 
x 
 
 
 
 
 
 
Medicine hand-
out 
 
 
x 
 
 
 
 
 
 
 
Compliance 
assessment 
 
 
 
 
 
 
 
 
 
x 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
  
*Telephone visit 
**Urine-hCG is measured at home 
 
6.3 Protocol specific procedures  
Key secondary outcomes: 
Level of Tenderness: Measured using a handheld pressure algometer. Points measured is right 
quadriceps 15 cm from apex patella, and left trapezius 10 cm acromion (between acromion and 
C6/7). Each point is measured 3 times; point 2 and 3 is measured 1 cm above and 1 cm below the 
first point. 
 
 
Exploratory secondary outcomes: 
Pain Sensitivity: Standardized assessment of experimental pressure pain sensitivity is performed at 
baseline and after 12 weeks of treatment. Assessments are conducted as recommended by the 
’International Association for the Study of Pain’. Computer-controlled cuff algometry is performed 
on lower legs in all patients to assess pressure pain threshold and pressure pain tolerance.  
 
Inhibition (CPM) and augmentation (TSP) of pain: Standardized assessment of experimental 
efficiency of the pain modulatory systems is performed at baseline and after 12 weeks of treatment. 
Assessments are conducted as recommended by the ’International Association for the Study of 
Pain’. Computer-controlled cuff algometry is performed on lower legs in all patients to assess 
temporal summation of pain (TSP: increase in pain scores to ten repeated stimulations), and 
conditioned pain modulation (CPM: increase in pressure pain threshold during cuff pain 
conditioning on the contralateral leg). 
 

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Standardized assessment of experimental pressure pain sensitivity has shown good reliability, and 
provides insights into the pathophysiological mechanisms involved in the pain condition. 
 
Muscular exhaustion: Measured by asking the participant to complete an isometric muscle 
exhaustion task by maintaining 90° shoulder abduction (dominant arm) for as long as possible with 
the elbow extended and the hand pronated (hand facing downwards). The participants will be seated 
on a chair without armrests and both feet placed on the floor. An observer will assess the quality of 
the test by looking for compensations (e.g. shoulder shrugging or lateral flexion of trunk) and 
correct the participant. Task failure (test position can no longer be maintained) defines the test 
duration. The participants are instructed to maintain the position until they feel maximal muscle 
exhaustion (corresponding to a score of 10 on a 0-10 scale with 0 being “no muscle fatigue” and 10 
being ‘maximal muscle fatigue/exhaustion’). Before and immediately after the test, the participants 
are asked to rate the current shoulder pain intensity on a 0-100 visual analogue scale (VAS), with 
anchors 0 = ”no pain” and 100 = ”worst pain”. Surface electromyography (EMG) will be recorded 
from the anterior, middle and posterior deltoid muscle at 3000 Hz during the entire test. From the 
EMG recordings during the exhausting test the root mean square (RMS) amplitude and median 
power frequency (MPF) will be calculated in 1 second epochs, using a fast Fourier transform 
algorithm. The 1 second epochs will be normalised against their respective initial values (iMPF and 
iRMS), calculated as the mean of the first 5 seconds and set to 100%. Normalised MDF (nMPF) 
and RMS amplitudes (nRMS) at 50% of test duration (halfway +/- 2.5 seconds) will be calculated 
as a percentage of the initial values (iMPF and iRMS). nMPF and nRMS at the end of the test 
(exhaustion) will be calculated as the mean of the last 5 seconds.  
Outcomes measured: 
1) Duration of the test (from start to exhaustion) 
2) Change in shoulder pain intensity (0-100 visual analogue scale) from before to immediately 
after the test 
3) Change from first 5 seconds to last 5 seconds in surface EMG nRMS 
4) Change from first 5 seconds to last 5 seconds in surface EMG nMPF 
5) Change from first 5 seconds to middle 5 seconds in surface EMG nRMS 
6) Change from first 5 seconds to middle 5 seconds in surface EMG nMPF 
 
Physical fitness: Measured by the 30 second chair stand test. The test starts with the subject seated 
on a chair with her back touching the backrest. Subjects rise to a full stand with the back straight 
and then sit down again to regain this cycle as many times as they can within 30 seconds. Arms 
have to be crossed over the chest during the test. Before the test, subjects are asked to perform one 
repetition to familiarize with the procedure.  
 
Biological material 
Blood for a bio bank will be collected at baseline and after 12 weeks of treatment. There will be 
stored 2 x 0.5 ml serum and 2 x 0.5 ml plasma in the bio bank collected at both baseline and after 
12 weeks of treatment, for later analysis of inflammatory cytokines.  
 
6.4 Rules for concomitant medication/treatment during the trial 
The participants are not allowed to use opioids, NSAIDs or medication with anti-inflammatory 
effects. The participants are allowed to continue with paracetamol, pregabalin, gabapentin, 
antidepressants, baclofen or tizanidin but the dosing must remain stable 4 weeks before and during 
the trial. The participants are not allowed to receive any new pain medication during the trial. 

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6.5 Measures to promote compliance 
Participants will receive a daily SMS reminder about taking their trial medication. At all visits, 
empty medicine cans are returned and non-ingested tablets are counted. The participants are 
considered non-compliant if the trial medication is  not taken at least 80% of the trial period. 
 
6.6 Treatment of subjects after termination of the study 
At the follow-up visit, future treatment can be discussed with the primary investigator, and 
treatment with LDN in an individual dosing is offered. 
 
7. Outcome measures 
7.1 Specification and justification of outcome measures 
Previous studies have found that 57-60% of patients with FM treated with LDN for 8-12 weeks 
report a more than 30% decrease in pain. We have chosen change in pain intensity between baseline 
and 12 weeks of treatment, measured on a 0-10 NRS (FIQR item) to be the primary outcome. 
 
As key secondary outcomes we have chosen other core FM 
symptoms/domains as recommended by the Outcome Measures in Rheumatology Clinical Trials 
(OMERACT) guidelines [34]. These symptoms/domains constitutes: Impact of fibromyalgia, level 
of pain, level of tenderness, level of fatigue, level of sleep disturbance, level of depression, level of 
anxiety, level of stiffness, level of cognition and level of physical function. These 
symptoms/domains are evaluated based on single FIQR items, FIQR subscales and FIQR total 
score. Level of tenderness is also assessed using a handheld pressure algometer. FIQR is a validated 
questionnaire often used to evaluate symptom burden and fluctuations in the disease of FM [28]. 
The FIQR asks patients to rate how difficult it is to perform a list of 9 common activities over the 
previous 7 days on an 11 point scale (ranging from "no difficulty" to "very difficult"). The FIQR 
then asks patients to indicate how often their fibromyalgia impacts their quality of life over the last 
7 days on an 11 point scale (ranging from "never" to "always"). Finally, the FIQR asks patients to 
assess the severity of 10 different symptoms on an 11 point scale (ranging from no symptoms to 
extreme symptoms). These three sub-scales are summed to represent an overall FIQR score. A 
lower score indicates lower severity. Other key secondary outcomes are global assessment, pain 
distribution, pain sensitivity and health-related quality of life. Global assessment will be made using 
the PGI-C scale. Pain distribution will be measured using the Widespread Pain Index (WPI). 
Assessments of pain sensitivity are conducted as recommended by the ’International Association 
for the Study of Pain.’ EQ-5D is a validated instrument used to measure quality of life in both 
population based studies and in the study of various acute and chronic diseases [35]. 
 
Exploratory secondary outcomes are changes in muscular exhaustion, physical fitness, 
pain inhibition, pain augmentation and level of inflammatory cytokines. From the clinical 
experience with LDN, patients often report improvement of early muscular fatigue and better daily 
functioning. To be able to evaluate such possible effects we have chosen to include some 
explorative outcome parameters. Effect on daily functioning will be evaluated using the function 
domain of the FIQR. To evaluate a possible improvement of muscular exhaustion and physical 
fitness a muscular exhaustion test of the deltoid muscle [12] and a 30-second chair stand test will be 
carried out [36]. Assessments of pain inhibition and pain augmentation are conducted as 
recommended by the ’International Association for the Study of Pain.’ Level of relevant pro-
inflammatory cytokines will be measured.   
 

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7.2 Methods and times for measurement, registering and analysis of outcome measures 
Demographic data are collected at screening.  
Questionnaire data for phenotyping of patients are collected at screening (PHQ, GAD). 
Questionnaire data that are used as outcome measures are collected at baseline (week 0) and after 4, 
8 and 12 weeks of treatment and at follow up (FIQR, EQ-5D, PGI-C, ACR2016).  
Protocol specific procedures: Pain sensitivity, CPM/TSP, 30-second chair stand test and muscle 
exhaustion test of the deltoid muscle are measured at baseline and after 12 weeks of treatment.  
Blood tests and ECG are collected at screening and after 12 weeks of treatment. 
Safety data are collected at all visits 
 
When the trial is terminated, and primary statistical analysis has been performed the investigators 
are unblinded. Changes in outcome measures are compared between the active versus the placebo 
group.  
 
8. Safety evaluation 
8.1 Specification and justification of safety parameters 
As mentioned in section 2.4 the study medication is considered safe to use and the risk of serious 
adverse drug reactions is considered to be very small. Liver function and kidney function is 
monitored during the trial, measuring ALAT, bilirubin, Creatinine and GFR at screening and after 
12 weeks of treatment. Thrombocyte function is measured at screening and after 12 weeks of 
treatment. Heart function is monitored by measuring ECG at screening and after 12 weeks of 
treatment. Urine-hCG is measured with a sensitivity of minimum 25 mIU/ml at baseline (week 0) 
and after 4, 8 and 12 weeks of treatment in all fertile women. At 4 and 8 weeks, the participants will 
take the pregnancy test at home.  
 
8.2 Procedures for registration and reporting of adverse events/adverse reactions 
Definitions:  
 
Adverse event (AE): any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment  
 
Adverse reaction (AR): All untoward and unintended responses to an investigational 
medicinal product related to any dose administered.  
 
Unexpected adverse reaction: an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator's Brochure for an 
unauthorised investigational product or summary of product characteristics for an authorised 
product).  
 
Serious adverse event (SAE) or serious adverse reaction (SAR): any untoward medical 
occurrence or effect that at any dose results in death is life-threatening, requires 
hospitalisation or prolongation of existing hospitalisation, results in persistent or significant 
disability or incapacity, or is a congenital anomaly or birth defect.  
 
Serious unexpected suspected adverse reactions (SUSAR): an adverse reaction that is both 
unexpected and serious 
AE and AR are registered at baseline (week 0) after 2, 4, 8 and 12 weeks of treatment and at the end 
of follow-up (week 16).  

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The SmPC for Naltrexone 50 mg is used as reference document when assessing AE and AR. 
 
8.3 Arrangements for avoiding and treating complications 
Complications as a result of the treatment are not expected.  
 
8.4 Statement of how and how long the trial participants should be monitored in case of adverse 
events/adverse reactions  
The participants are offered follow up at the primary investigator until adverse events/adverse 
reactions have ceased or are stable.  
 
8.5 Reporting of suspected unexpected serious adverse reactions 
 Investigator must report all serious adverse events (SAE) to sponsor immediately but no 
later than 24 hours after the event. All SAE’s are registered in a SAE formula which is sent 
without delay to sponsor by e-mail. In the SAE formula investigator will also report 
suspected causality. 
 Causality of a SAE shall be determined according to CT-3 guidelines. All adverse events 
judged by either the investigator or the sponsor as having a reasonable suspected causal 
relationship to an investigational medicinal product qualify as adverse reactions. The 
causality assessment given by the investigator should not be downgraded by the sponsor. If 
the sponsor disagrees with the investigator’s causality assessment, both the opinion of the 
investigator and the sponsor should be provided with the report. 
 If a SAR is assessed as unexpected according to the SmPC, sponsor must unblind the 
subject before reporting it to the Danish Medicines Agency. A copy of the randomization 
list will be stored behind double lock at the office of the sponsor. PI is not unblinded, except 
in case of a medical emergency and only if PI finds it necessary to ensure the safety of the 
subject. PI can unblind a single subject by breaking the individual code-envelope related to 
the subjects blinding code. The code-envelopes will be stored together with the trial 
medicine at the site of the trial and will be available 24/7.  
 Under section 89(2)(i) of the Danish Medicines Act, the sponsor must immediately inform 
the Danish Medicines Agency if any suspected unexpected and serious adverse reactions 
occur during the trial.  
 The sponsor must ensure that all relevant information about suspected unexpected serious 
adverse reactions (SUSAR), which are fatal or life-threatening, is recorded and reported to 
the Danish Medicines Agency as soon as possible, and no later than 7 days after the sponsor 
is informed of such a suspected adverse reaction. No later than 8 days after the reporting, 
must the sponsor inform the Danish Medicines Agency of relevant follow-up information on 
the sponsor's and the investigator's follow-up action to the reporting. Any other suspected 
unexpected serious adverse reactions must be reported to the Danish Medicines Agency no 
later than 15 days from the time when the sponsor is informed about them. All reports must 
be accompanied by comments on possible consequences for the trial.  
 Reporting of SUSAR is done by filling in and submitting the Danish Medicines Agency's e-
form for reporting of non-commercial sponsors of suspected unexpected serious adverse 
reactions (SUSARs) seen in clinical trials. 
 Once a year throughout the duration of the clinical trial, the sponsor must provide a list of 
all suspected serious adverse reactions which have occurred during the trial period and a 

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report on the trial subjects' safety. The list and the report must be submitted to the Danish 
Medicines Agency and the Ethical Committee.  
 No more than 90 days after completion of a trial, the sponsor must inform the Danish 
Medicines Agency that the trial has been completed. As soon as possible and no later than 
one year after the trial has ended, the trial results must be entered in EudraCT. 
Subsequently, data will be published on www.clinicaltrialsregister.eu 
8.6 Safety related to the COVID-19 pandemic  
Because of the COVID-19 pandemic, the Danish Medicines Agency in October 2020 demanded 
that all clinical trials in Denmark should take precautions to reduce the risk of infection with 
COVID-19 for trial participants. It was therefore decided to re-schedule the 4, 8, and 16-week 
follow-up visits as telephone visits, to reduce traveling and contact with trial personnel. As a 
consequence, vital signs could only be performed at baseline and 12 weeks follow-up. As there was 
no reasonable suspicion that vital signs would be influenced by the trial medication, this change 
was deemed safe for the participants.  
 
9.Statistics 
9.1 Description of the statistical methods 
Our main analysis will be calculation of between group differences in the continuous outcomes 
such as change scores for primary and key secondary outcomes using Repeated-Measures Analysis 
of Covariance (ANCOVA) procedures based on linear mixed model, which is valid under the 
assumption that missing data is missing at random. In an ANCOVA any potential between group 
differences at baseline will be adjusted for subsequently in the statistical analysis by adjusting for 
the level at baseline. Secondarily an analysis of number of responders in the two groups will be 
carried out. A responder is defined as a participant who reports a more than 15%, 30%, and 50% 
decrease in pain after 12 weeks of treatment with LDN.  For these dichotomous outcomes logistic 
regression will be used to calculate relative differences between the two groups. The prespecified 
efficacy analyses will be based on the data for full analysis set; the intention-to-treat (ITT) 
population, which includes all participants that are assessed and randomized at baseline. In the case 
of missing data during the 12 week trial, repeated measure linear mixed models will adjust for that 
indirectly. In order to confirm the robustness of the findings for the primary and key secondary 
outcomes, sensitivity analyses will be performed to the primary analyses, including the (i) ‘As 
Observed’ population (assuming data were missing completely at random), (ii) non-responder 
imputation (using baseline observation carried; potentially valuable if data is not missing at 
random), and (iii) the ‘Per Protocol’ population. 
 
Per protocol population will be defined as: Participants with an adherence to the treatment of at 
least 80%. 
 
9.2 Trial interpretation 
The trial is considered a success if the improvement of the primary outcome is significantly higher 
in the active group than in the placebo group, defined as the 95% confidence interval being above 
zero and the significance level being below 0.05. The trial is considered inconclusive if the 
improvement of the primary outcome is not reaching a significant level. The trial is considered 
negative if the improvement of the primary outcome is higher in the placebo group regardless of the 
significance level.  

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10. Direct access to sourcedata/sourcedocuments 
According to the Danish executive order on GCP, informed consent from the subjects will also 
include consent to monitoring, auditing and/or inspection. Investigator is authorized to direct access 
source data/documents (including patient’s files) in connection with monitoring, auditing and/or 
inspection by a scientific ethics committee, the Danish Medicines Agency or by health authorities in 
other countries.  
 
11. Quality control and quality assurance 
It is confirmed that ordinary procedures for quality control and assurance are complied with, cf. 
sections 3 and 4 in the Danish executive order on GCP.  
 
12. Ethics 
12.1 Ethical considerations 
Approval has been obtained from The Danish Data Protection Agency. Data security will be 
maintained for 5 years and afterwards all data will be stored according to rules and regulations 
specified by the Danish Data Protection Agency.  
The trial is initiated by the investigators. Neither investigators nor subjects have any 
economic interests in the trial.  
Half of the participants will receive active treatment with LDN and half of them will 
receive placebo. A parallel group design was chosen to reduce bias and secure a trial with good 
internal validity (i.e. scientific credibility).  
The participants are at risk of having side effects from the study medication. No 
serious adverse reactions have ever been reported during treatment with LDN. Side effects expected 
most likely to occur are: Headache, vivid dreams, nausea, diarrhea and abdominal pain.  
Potential benefits for the participants are that they might experience reduced 
tenderness, reduced pain, improved sleep, improved energy and improvement in daily functioning. 
All participants regardless if they received active treatment or placebo will be offered treatment 
with LDN in an individual dosing after termination of the trial. The results from the study will be of 
benefit for other patients with FM.  
 
12.2 Recruitment, information and collection of informed consent 
Participants for the trial are partly recruited among patients who have been referred to treatment at a 
public pain center in the Southern Region of Denmark, and partly from advertising in relevant 
printed or internet media.  
Participants recruited from the pain clinic will receive written information about the 
trial from their nurse or physician. For participants recruited via advertising, written information is 
send by e-mail. For all participants, oral information is given by telephone by the Principal 
Investigator. It is emphasized that participation is voluntary, and that consent can be withdrawn at 
any time. The participant is given a minimum of 24 hours of reflection, before informed consent is 
collected. Before informed consent is collected oral information about the trial is repeated. The 
participant is informed that she has the right to bring an assessor, when receiving oral information 
about the trial. It is secured that the information can be given in privacy. 
 
13. Handling and filing of data and biological material 
13.1 Handling of data 

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Data obtained from the participants file will be data about concomitant medication from the shared 
medication record and laboratory data (blood tests and ECG). No data will be obtained from the 
participants file, before informed consent is given. 
Questionnaire data are entered directly into the eCRF in RedCap by the participants. 
All other data are entered into the eCRF in RedCap by the primary investigator or the study nurse.    
Later data will be transferred to a statistical program for analyzing.  
5 year after termination of the study, the data will be anonymized.  
 
13.2 Handling of biological material 
Blood for a research bio bank will be collected at baseline and after 12 weeks of treatment. The 
purpose of the bio bank is to be able to measure a possible reduction in proinflammatory cytokines 
in participants receiving active treatment compared to placebo. For this purpose, 2 x 0.5 ml serum 
and 2 x 0.5 ml plasma is collected at baseline and after 12 weeks of treatment.  
Any excess blood will be stored for 10 years. After 10 years the blood will be destructed. 
The blood in the bio bank will be destructed no later than 01.01.2030. 
Informed consent to perform analyzes for other research purposes are collected from all 
participants. 
 
14. Financing and insurances 
14.1 Insurance 
The participants are covered by the governmental patient insurance, which includes all patients in 
the Danish health care system. 
 
14.2 Financing 
Salary: 
Salary for the primary investigator is covered by Ph.D. salary.  
 
TAP: 
Salary for study nurse (780 hours) 
 
                   260.000 Dkr 
 
 
 
 
Operating expenses: 
Trial medication 
 
 
                    150.000 Dkr 
GCP monitoring 
 
 
 
20.000 Dkr 
Database 
 
 
 
 
30.000 Dkr 
Compensation to subjects for transport   
                    300.000 Dkr 
ECG, blood tests, bio bank, s-naltrexone 
 
100.000 Dkr 
Apparatus, software etc.   
 
 
10.000 Dkr 
 
Total 
 
 
 
                    870.000 Dkr  
  
 
Funding of operating expenses has been granted from The Danish Reumatism Association with a 
grant of 175.000 Dkr. The grant will be transferred to a separate research account for the project 
(account number: 10224731). 
 
Funding will be applied for from other relevant public and private funds.  
 

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14.3 Compensation for subjects 
Subjects that reside more than 25 kilometers away from the place of the trial, will receive 
compensation for expenses for transportation. The compensation fee is 1.97 Dkr per kilometer and 
it is tax free. 
 
15. Publication 
Information about the trial is published at ClinicalTrials.gov and EUDRACT before enrolment of 
the first patient.  
The protocol will be published in an international peer-reviewed journal (e.g. Trials, or BMJ Open). 
Results from the study is planned to be published in high impact international peer-reviewed 
journals. Both positive, negative, and inconclusive results will be published. All data will be 
anonymized.  
 
First author will be Karin Due Bruun.  
Last author will be Palle Toft. 
Co-authors will be all Co-investigators that fulfill the following criteria: 
 Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND 
 Drafting the work or revising it critically for important intellectual content; AND 
 Final approval of the version to be published; AND 
 Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved. 
 
 
 
16. Appendix 
Appendix 1: ACR-1990 criteria (in Danish) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1 
 
ACR-1990 kriterier for fibromyalgi 
 
 
Følgende skal være opfyldt: 
 
Udbredte smerter (axialt + alle 4 kropskvadranter) 
 
 
ja / nej 
Varighed min 3 måneder  
 
 
 
ja / nej 
Ikke anden sygdom der kan forklare smerterne 
 
 
ja / nej 
 
Smerter ved 4 kg tryk på 11 ud af 18 tenderpoints: 
 
Occiput: bilateralt ved insertion af suboccipital muskulatur 
Lavt cervicalt: bilateralt ved den forreste del af det intertransversale rum ved C5-C7 
Trapezius: bilateralt på midten af den øverste del 
Supraspinatus: bilateralt ved udspring på scapula tæt ved den mediale kant 
Anden ribben: bilateralt ved 2. costokondrale ledforbindelse, lige lateralt for leddene 
Lateral epikondyl: bilateral, 2 cm distalt for epikondylerne 
Gluteal: bilateralt i den øverste, laterale kvadrant af balderne i den anteriore del af muskulaturen 
Trochanter major: bilateralt, lige posteriort for trochanter major prominens 
Knæ: bilateralt ved den mediale fedtpude lige proksimalt for ledlinjen 
 
 
 
 
Højre 
 
Venstre 
 
Occiput 
 
_____ 
 
_____ 
 
Cervicalt 
 
_____ 
 
_____ 
 

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Trapezius 
 
_____ 
 
_____ 
 
Supraspinatus 
_____ 
 
_____ 
 
2. ribben 
 
_____ 
 
_____ 
 
Lateral epikondyl 
_____ 
 
_____ 
 
Glutealt 
 
_____ 
 
_____ 
 
Trochanter major 
_____ 
 
_____ 
 
Knæ 
 
_____ 
 
_____ 
 
 
Ialt 
_____ 
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