Melatonin fOr CHronic bAck Pain (The MOCHA Trial): A Randomized, Double Blind, Placebo-controlled Trial
Phase: PHASE3
Conditions: Back Pain Lower Back Chronic, Insomnia
Sponsor: Odense University Hospital

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Clinical Trial Protocol 
 
 
 
Melatonin fOr CHronic bAck pain (The MOCHA trial): 
A randomized, double blind, placebo-controlled trial 
 
In Danish:  
Melatonin til kroniske rygsmerter (MOCHA studiet) 
 
 
 
Version: 
 
 4.0 .  
Date:                                    26.08.2024 
EU CT number: 
2023-503530-41-00 
Clinicaltrials.gov: 
NCT06476392 
Approved: 
 
December 3rd 2024 
 

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Table of contents: 
1.0 General information ......................................................................4 
1.1 Time plan ........................................................................................................................ 4 
1.2 Abbreviations ................................................................................................................. 5 
2.0 Background ....................................................................................6 
2.1 Trial background ........................................................................................................... 6 
2.2 Summary of results from previous trial on Melatonin for fibromyalgia and 
chronic back pain ................................................................................................................. 6 
2.3 Background information about Melatonin .................................................................. 7 
2.4 Known and potential side effects, risks and possible benefits for the subjects ........ 7 
2.5 Description and justification for dose, dose regimen and treatment period .......... 11 
2.6 Description of study population .................................................................................. 11 
3. Study aim ........................................................................................11 
3.1 Hypothesis ..................................................................................................................... 11 
3.2 Aims and objectives ..................................................................................................... 11 
4. Study plan .......................................................................................12 
4.1 Study design .................................................................................................................. 12 
4.2 Trial procedures and study visits ............................................................................... 14 
4.3 Primary and secondary outcomes .............................................................................. 15 
4.4 Sample size estimation ................................................................................................. 18 
4.5 Measures for reduction in bias ................................................................................... 18 
4.6 Description of the study treatment ............................................................................. 18 
4.7 Description of expected time frame for the individual patient ................................ 18 
4.8 Rules for termination of the study .............................................................................. 19 
4.9 Procedures for accounting for the trial medicine, including placebo products ..... 19 
4.10 Source data ................................................................................................................. 19 
5. Selection and withdrawal of participants ...................................19 
5.1 Selection and screening of patients ............................................................................. 19 
5.2 Inclusion criteria .......................................................................................................... 20 
5.3 Exclusion criteria ......................................................................................................... 20 
5.4 Procedures for withdrawal.......................................................................................... 21 
6. Patient treatment ...........................................................................21 
6.1 Detailed description of the study treatment .............................................................. 21 
6.2 Off label use .................................................................................................................. 22 
6.4 Rules for concomitant medication/treatment during the trial ................................. 22 
6.5 Measures to promote compliance ............................................................................... 22 

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6.6 Treatment of patients after termination of the study ............................................... 22 
7. Outcomes ........................................................................................22 
7.1 Study outcome measures ............................................................................................. 22 
7.2 Description of specific assessment procedures .......................................................... 23 
7.2.1 Patient-reported outcomes: .................................................................................... 23 
7.2.2 Pressure pain thresholds (PPT) .............................................................................. 23 
7.2.3 Physiological sleep metrics (subgroup of 60 patients) ........................................... 23 
8.0 Safety evaluation..........................................................................25 
8.1 Specification and justification of safety parameters ................................................. 25 
8.2 Procedures for registration and reporting of adverse events/adverse reactions .... 25 
8.3 Arrangements for avoiding and treating complications........................................... 26 
8.4 Monitoring of patients in case of adverse events/adverse reactions ........................ 26 
8.5 Reporting of serious adverse events and unexpected serious adverse events......... 26 
9.0 Statistics ........................................................................................27 
9.1 Statistical methods ....................................................................................................... 27 
9.2 Trial interpretation ...................................................................................................... 28 
10. Direct access to source data/source documents ........................29 
11. Quality control and quality assurance ......................................30 
12. Ethics ............................................................................................30 
12.1 Ethical considerations ................................................................................................ 30 
12.2 Recruitment, information and collection of informed consent .............................. 30 
13. Handling and filing of data and biological material ................31 
13.1 Handling of data ......................................................................................................... 31 
13.2 Handling of biological material ................................................................................ 31 
14. Financing and insurances ...........................................................31 
14.1 Insurance .................................................................................................................... 31 
14.2 Financing .................................................................................................................... 31 
14.3 Compensation for patients ........................................................................................ 32 
15. Publication....................................................................................32 
17. References ............................................................................... 3233 
 

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1.0 General information 
 
The trial will be carried out according to this protocol, ICH-GCP guidelines, national 
regulatory requirements and legislation. 
 
Sponsor and primary investigator 
Karin Due Bruun, MD, Consultant 
Pain Research Group, Pain Centre  
Department of Anesthesiology and Intensive Care 
Odense University Hospital 
Heden 7-9 
5000 Odense C 
 
 
 
 
 
 
 
 
GCP-monitoring 
GCP-unit Odense University Hospital 
Department of Clinical Biochemistry and Pharmacology 
J.B. Winsløwsvej 9A, 3rd floor 
5000 Odense C 
 
Pharmacy 
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 
Department of Anesthesiology and Intensive Care 
Odense University Hospital 
Heden 7-9  
5000 Odense C 
 
1.1 Time plan 
Approval from authorities:  
 
 
 
14.03.2024 
Expected first act of recruitment:                                                                             01.08.2024 
Expected start of inclusion:  
 
 
                     01.10.2024 
Expected end of inclusion:  
 
  
                     31.08.2026 
Expected end of follow-up:  
 
 
                     01.11.2026 
Expected submission of papers: 
 
 
                     01.05.2027 
 
 
 
 

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1.2 Abbreviations 
 
AASM = American Academy of Sleep Medicine 
AE = Adverse events 
ALAT = Alanine-aminotransefase 
AR = Adverse reaction 
CTCAE = Common Terminology Criteria for Adverse Events 
E-CRF = Electronic case report form 
EEG = Electroencephalography 
GCP = Good Clinical Practice 
GFR = Glomerular-filtration-rate 
GPE = Global Perceived Effect 
hCG = Human chorionic gonadotropin 
IrOx = Iridium oxide 
ISI = Insomnia Severity Index 
N1 = Non-rapid eye movement stage 1 
N2 = Non-rapid eye movement stage 2 
N3 = Non-rapid eye movement stage 3 
NSAID = Non-steroidal anti-inflammatory drug  
OPEN = Odense Patient data Explorative Network 
PPT = Pain Pressure Threshold 
PROM = Patient Reported Outcome Measure 
PROMIS-10 = Patient-Reported Outcomes Measurement Information System 
REM = Rapid eye movement 
RMQ = Roland Morris Disability Questionnaire 
SAE = Serious adverse event 
SAP = Statistical analysis plan 
SAR = Serious adverse reaction 
SE = Sleep efficiency 
SmPC = Summary of Product Characteristics 
SOL = Sleep onset latency 
SPT = Sleep period time 
SUSAR = Serious unexpected suspected adverse reactions 
TST = Time from sleep onset until final awakening 
WASO = Wake after sleep onset 
WHO = World Health Organization 
 
 
 
 
 

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2.0 Background 
 
2.1 Trial background 
According to the World Health Organization (WHO) Global Burden of Disease study, back pain is 
one of the conditions impacting disability the most worldwide.1,2 Pain medication use in 
patients with chronic back pain is substantial, but the efficacy of commonly used analgesics 
such as paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), muscle relaxants and 
opioids compared with placebo are modest, with effects typically less than 10 points on a 0-
100 pain scale 3-5. Importantly, these analgesics are not harmless due to gastrointestinal and 
cardiovascular side-effects (NSAIDs) and risk of dependency and addiction (opioids) 3-5. This 
often leave general practitioners without good treatment options for many patients with 
chronic low back pain. 
 
More than half of patients with chronic back pain also have sleep problems (i.e. 
insomnia),6,7 which negatively affect daily function, general health and quality of life.  
Research suggest that insomnia has negative effects on pain processing, and although the 
relationship between pain and insomnia is bi-directional, insomnia is considered to be a 
stronger predictor of pain than pain for the development of insomnia.8,9 
 
Melatonin is a widely available drug worldwide, and well known for its use in 
people with sleep disorders and jetlag. Melatonin is a naturally occurring hormone excreted 
by the pineal gland that is part of regulating the circadian rhythm (sleep-wake patterns).10  
Unlike commonly used drugs to treat back pain, the safety profile of melatonin is favorable 
with no adverse events of major clinical significance reported in the treatment of sleep 
disorders.11,12 In recent years, some preliminary studies have showed a promising effect of 
Melatonin for treatments of pain (i.e. as pain medication). A meta-analysis reported an effect 
size of 0.65 (95%CI 0.34 to 0.96) of Melatonin (doses ranging between 3-10 mg before sleep) 
compared with placebo in reducing pain in patients with non-musculoskeletal chronic pain 
(e.g. migraine, irritable bowel syndrome, burning mouth syndrome), suggesting that 
Melatonin could potentially also be a valid treatment option for chronic musculoskeletal pain 
patients.13  
Given the effect of Melatonin on sleep and the potential effect of Melatonin on pain,14 
we also plan to explore the potential mediating effect of Melatonin on pain through 
improvement of sleep. 
 
2.2 Summary of results from previous trial on Melatonin for fibromyalgia and chronic 
back pain 
Based on previous systematic reviews,15,16 we have identified 4 studies on Melatonin for 
patients with fibromyalgia and chronic musculoskeletal pain. However, most of the studies 
had no placebo comparator. 
One Russian study,15 including 178 patients aged 40–65 years with chronic back pain 
(>3 months pain) had 6 treatment groups, that were analyzed in 3 comparisons. The effect of 
Melaxen® 3 mg (Melatonin) as an add on treatment to Artra® (Unipharm Inc.; combination 
of 500mg glucosamine hydrochloride and 500mg chondroitin sulfate) and/or diclofenac 
(NSAID) was explored. In comparison 1, treatment with Artra one tablet twice daily for 1 
month, followed by Artra one tablet once daily for 2 months (n=29) was compared to the 
same treatment regime plus Melaxen 3 mg 30-40 minutes before bedtime (n=31). In 
comparison 2, treatment with Artra one tablet twice daily plus diclofenac 25 mg 2-3 times a 
day (n=30) was compared to the same treatment regime plus Melaxen 3mg 30-40 min before 
sleep (n=30). In comparison 3, treatment with diclofenac 25 mg three times a day (n=29) was 
compared to the same treatment regimen plus Melaxen 3mg 30-40 min before sleep (n=29). 

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Overall, the results favored groups receiving Melaxen (Melotonin) with better results 
regarding pain, function, anxiety and sleep. 
An Iraqi study,17 examined the effect of Melatonin (3 mg/day or 5 mg/day) in addition 
to an antidepressant (Fluoxetine 20 mg/day) over 8 weeks. The study included 101 patients 
(18-65 years) with fibromyalgia according to the American College of Rheumatology (ACR) 
1990 classification criteria. Participants were randomized to one of 4 groups: 1) Fluoxetine 
20 mg/day; 2) 5mg/day Melatonin; 3) 3mg/ day Melatonin + Fluoxetine 20 mg/day; 4) 5mg/ 
day Melatonin + Fluoxetine 20 mg/day. Melatonin groups experienced the largest within 
group changes in pain, but no between group statistical analysis was performed hampering 
the interpretation of these results. 
A Brazilian study,14 compared 3 groups over six weeks. The study included 63 
patients (mean age about 50 years) with fibromyalgia according to the ACR 1990 criteria. 
Group 1 received 25 mg Amitriptyline (an antidepressant) + placebo; group 2 had 10 mg 
Melatonin + placebo; and group 3 had 25 mg Amitriptyline + 10 mg Melatonin. Both groups 
receiving Melatonin had significantly larger reductions in pain compared to the Amitriptyline 
alone group. 
Finally, a Spanish study,18 including patients with fibromyalgia (patients aged 40-60 
years) investigated the dose-response relationship of 10-day periods with progressively 
higher of doses of Melatonin (3, 6, 9, 12 and 15mg Melatonin), separated by 10-day placebo 
wash-out periods on several outcomes, including pain. Doses of 9, 12 and 15mg Melatonin 
all resulted in decreased pain compared to baseline and the initial placebo period, this was not 
observed for 3 and 6mg doses. 
 
The above-mentioned previous studies of melatonin had a treatment duration varying from 10 
days to 8 weeks. The study with 10 days duration was a dose-response study, whereas the 
three efficacy studies had a treatment duration varying from 4 to 8 weeks. We have chosen 6 
weeks treatment as it corresponds to the average treatment duration of the previous RCT 
studies. Furthermore, we want to ensure that the treatment duration is long enough to 
potentially improve sleep quality, so we can explore whether the pain relieving effect of 
Melatonin is mediated by an improvement of sleep.  
 
2.3 Background information about Melatonin 
Melatonin is a naturally occurring hormone excreted by the pineal gland and play a role in 
regulating the circadian rhythm (sleep-wake patterns) 10. Melatonin is primarily marketed for 
sleep disorders and jetlag. In many countries, Melatonin is an over-the-counter drug, but 
require prescription in Denmark. In Denmark, the indications for prescription are: 1) short 
term treatment of insomnia/poor sleep quality in patients older than 55 years; 2) short term 
treatment of jetlag in adults; and 3) insomnia in children/adolescents with autism and/or 
Smith-Magenis syndrome.19 The recommended dose is between 2 and 10 mg depending on 
the indication. In this trial, we will test a dose of 10 mg of oral Melatonin for off label use to 
treat pain in patients with chronic back pain (with and without insomnia). 
 
2.4 Known and potential side effects, risks and possible benefits for the subjects 
Risks: 
For patients with sleep disorders and insomnia, Melatonin has been shown to be well-
tolerated in clinical studies, with no evidence of serious adverse events.11,12 Known side 
effects of Melatonin is listed in the Summary of Product Characteristics (SmPC) below. In 
this study a dose of 10 mg will be used, and the risk of serious adverse events when using this 
dose for treating pain is considered minimal. 
 

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Benefits: 
The potential benefit for the participants is a reduction in pain intensity, and improved sleep 
for those patients who suffer from insomnia in addition to chronic back pain. The results from 
this study has the potential to improve treatment for future patients with chronic low back 
pain. 
 
SmPC for Melatonin (ATC-code N05CH01): 
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) 
Table 1 
MedDRA system organ class  
 
Infections and infestations 
Rare 
 
Herpes zoster 
Blood and lymphatic system disorders 
Rare 
 
Leukopenia, 
thrombocytopenia 
Immune system disorders 
Not known 
 
Hyper-sensitivity reaction 
Metabolism and nutrition disorder 
Rare 
 
Hypertriglyceridaemia, 
hypocalcaemia, 
hyponatraemia 
Not known 
Hyperglycemia 
Psychiatric disorders 
Uncommon 
 
Irritability, 
nervousness, 
restlessness, 
insomnia,  
abnormal dreams,  
nightmares, 
anxiety 
Rare 
Mood altered, 
aggression,  
agitation, 
crying,  
stress symptoms, 
disorientation,  
early morning awakening, 
libido increased, 
depressed mood, 
depression 
Nervous system disorders 
 

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Common 
Headache, 
somnolence 
Uncommon 
Migraine, 
lethargy, 
psychomotor 
hyperactivity, 
dizziness 
Rare 
Syncope,  
memory impairment, 
disturbance in attention,  
dreamy state, 
restless legs syndrome, 
poor quality sleep, 
paraesthesia 
Eye disorders 
Rare 
 
Visual acuity reduced, 
vision blurred, 
lacrimation increased 
Ear and labyrinth disorders 
Rare 
 
Vertigo positional, 
vertigo 
Cardiac disorders 
Rare 
 
Angina pectoris, 
palpitations 
Vascular disorders 
Uncommon 
 
Hypertension 
Rare 
Hot flush 
Gastrointestinal disorders 
Uncommon 
 
Abdominal pain, 
abdominal pain upper,  
dyspepsia, 
mouth ulceration, 
dry mouth,  
nausea 
Rare 
Gastro-oesophageal reflux disease, 
gastrointestinal disorder,  
oral mucosal blistering,  
tongue ulceration, 
gastrointestinal upset, 
vomiting,  
bowel sounds abnormal, 
flatulence,  
salivary hypersecretion, 
halitosis,  
abdominal discomfort,  
gastric disorder,  
gastritis 
Hepatobiliary disorders 
Uncommon 
 
Hyperbilirubinaemia 

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Skin and subcutaneous tissue disorders 
Uncommon 
 
Dermatitis,  
night sweats,  
pruritus, 
rash,  
pruritus generalised,  
dry skin 
Rare 
Eczema,  
erythema, 
hand dermatitis, 
psoriasis,  
rash generalized,  
rash pruritic,  
nail disorder 
Not known 
Angioedema, 
oedema of mouth,  
tongue oedema 
Musculoskeletal and connective tissue 
disorders 
Uncommon 
 
 
Pain in extremity 
Rare 
Arthritis,  
muscle spasms,  
neck pain, 
night cramps 
Renal and urinary disorders 
Uncommon 
 
Glycosuria, 
proteinuria 
Rare 
Polyuria,  
haematuria, 
nocturia 
Reproductive system and breast 
disorders 
Uncommon 
 
 
Menopausal symptoms 
Rare 
Priapism,  
prostatitis 
Not known 
Galactorrhoea 
General disorders and administration site 
conditions 
Uncommon 
 
 
 
Asthenia,  
chest pain 
Rare 
Fatigue,  
pain,  
thirst 
Investigations 
Uncommon 
 
Liver function test abnormal,  
weight increased 
Rare 
Hepatic enzyme increased,  
blood electrolytes abnormal, 
laboratory test abnormal 
 

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2.5 Description and justification for dose, dose regimen and treatment period 
Dosages in previous identified trials evaluating Melatonin for fibromyalgia and chronic back 
pain have ranged between 3-15mg for 10-84 days.14,15,17,18 One of these trials18 including 
fibromyalgia patients (n=97) investigated the dose-response relationship (3, 6, 9, 12 and 
15mg Melatonin) of 10-day periods of Melatonin treatment separated by 10-day placebo 
wash-out periods. Doses of 9, 12 and 15mg Melatonin resulted in decreased pain compared to 
baseline and the initial placebo period, this was not observed for 3 and 6mg doses. Thus, for 
this trial we will administer a dose of 10mg Melatonin/day. The reason for choosing 10mg 
instead of 9mg is to reduce future burden on patients. Based on data from two reviews on the 
safety of higher doses of Melatonin, the use of 10 mg for a longer duration has not been 
associated with an increased frequency of SAE’s across a range of different clinical 
conditions.20,21 In Denmark, 3 and 5mg tablets are commercially available, choosing a dose of 
5mg will reduce the number of tablets to be taken from 3 to 2 compared with a 9mg dose (i.e. 
3 x 3mg tablets/day). 
The study medication (incl. placebo) will be prepared by Glostrup Pharmacy to ensure 
blinding of the study medication.  
 
The intervention group will receive two 5mg Melatonin tablets to be taken 30 min. before 
bedtime for 6 weeks. The control group will receive placebo tablets to be taken in the same 
manner, as the intervention group. In both groups, continued but not new co-interventions 
(e.g. pain medication use [such as paracetamol and NSAIDs], exercise therapy, manual 
therapy etc.) are allowed. This will be monitored by self-report questionnaire. 
 
2.6 Description of study population 
We will include patients aged 18-64 years with chronic back pain with and without insomnia 
in this trial. For specific in- and exclusion criteria please refer to section 5.2 and 5.3.  
3. Study aim 
3.1 Hypothesis 
Treatment with 10mg Melatonin will be superior in reducing pain intensity in chronic back 
pain patients compared with placebo. 
 
3.2 Aims and objectives 
The aim of this randomized double-blind placebo controlled clinical superiority trial is to 
investigate if daily treatment with Melatonin 10 mg once daily before bedtime for 6 weeks is 
superior compared with placebo in improving pain intensity assessed at 6 weeks after 
treatment initiation in patients with chronic back pain.  
 
The primary efficacy objective will be to compare the effect of the drug 
Melatonin, relative to placebo, on difference in change in pain intensity (i.e. average pain 
intensity past 7 days) measured on a 0-10 NRS scale, from baseline to 6 weeks in patients 
with chronic back pain. 
 
Our secondary efficacy objectives will be to compare the effect of drug 
Melatonin, relative to placebo, on 1) pain-related disability, 2) Global Perceived Effect 
(GPE), 3) insomnia, 4) health-related quality of life, and 5) pain sensitivity. Furthermore, 
trajectory (0 to 6 weeks) and responder indices from baseline to 6 weeks will be compared 
between the treatment groups for the primary outcome. 
 
Explorative objectives are to investigate sleep patterns as well as effect-
modification of presence/absence of comorbid insomnia. 

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4. Study plan 
4.1 Study design 
In this phase III trial we intend to investigate the efficacy of Melatonin for reducing pain 
intensity in patients with chronic back pain. To achieve the goal of testing efficacy, we will 
perform a randomized placebo controlled double blind clinical superiority trial. The study 
will include patients with chronic back pain with and without insomnia. Patients will be 
randomized to treatment with Melatonin or placebo (1:1 allocation ratio, random block size 
allocation), by a data manager outside the project. The data manager will prepare the 
randomization list in RedCap, and Glostrup Pharmacy will package the study medication 
according to this randomization list. 
 
Patients responding to trial advertisements will after an initial phone screening be invited to a 
clinical visit (visit 1) for patient information, assessment of eligibility and signing of 
informed consent. The study related examinations and procedures at visit 1 A will only be 
made if the participants sign the informed consent at the beginning of visit 1A. If the 
participants want to think whether to participate, they will at least have 24 hours 
consideration period, and the examinations listed at visit 1A will first be made, when the 
informed consent is signed. 
Patients consenting to participate and matching the eligibility criteria will be invited for a 2nd 
clinical visit (visit 2), where final decision on inclusion will be made. Included patients will 
then have baseline assessments performed, be randomized and study medication will be 
extradited. The trial period is 6 weeks (safety assessment in week 3 – phone), and with an end 
of follow-up phone call to patients for safety after 8 weeks from study start (Figure 1). 
 

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Figure 1: Study overview. 

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4.2 Trial procedures and study visits 
Detailed description of procedures and study visits: 
 
Initial patient screening (phone): 
- 
Initial eligibility criteria (see section 5.2 and 5.3 for in-/exclusion criteria) that can be 
assessed over the phone 
- 
Brief information about the study 
- 
Appointment for eligibility visit 1 (if potentially eligible after initial screening) 
 
Eligibility assessment (physical visit 1A): 
- 
Additional patient information and time for questions 
- 
Informed consent 
- 
Medical history 
- 
Vital signs (blood pressure, heartrate, weight, height) 
- 
Urine test (Human chorionic gonadotropin [hCG] for pregnancy) 
- 
Blood sample (Alanine-aminotransefase [ALAT], creatinine, Glomerular-filtration-
rate [GFR]) 
- 
Ear measurement for individual molding of ear electroencephalography (EEG) device 
(subgroup of 60 patients) – see section 7.2.3 for specific procedures on ear EEG. 
 
Ear EEG setup (physical visit 1B – subgroup of 60 patients): 
- 
Instruction and handing out ear EEG to patients 
- 
Start 7-day adaption period for sleeping with ear EEG (2 days with; 1 day without; 2 
days with; 2 days without) 
- 
After 7-day adaptation period – EEG sleep baseline assessment (5 out of next 7 days)  
(there must be 14 days between physical visit 1B and physical visit 2 to allow for 
adaptation period and baseline EEG measurement) 
 
Inclusion, baseline testing and randomization (physical visit 2): 
- 
Urine test (hCG for pregnancy) 
- 
Vital signs (blood pressure, heartrate, weight, height) 
- 
Study inclusion 
- 
Primary outcome 
- 
All other PROMs 
- 
PPT 
- 
Randomization 
- 
Handing out study medication 
 
Outcome assessment (Week 1): 
- 
Primary outcome 
 
Outcome assessment (Week 2): 
- 
Primary outcome 
 
Outcome and safety assessment (Week 3 – phone): 
- 
Primary outcome 
- 
ISI 
- 
Urine test (hCG for pregnancy) – at home 
- 
Questionnaire about adverse events 
- 
Phone call for adverse events and check of pregnancy test done 

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- 
Remind 60 patient EEG subgroup to start follow-up EEG sleep assessment in week 4 
 
Outcome assessment (Week 4): 
- 
Primary outcome 
- 
EEG sleep follow-up assessment (5 out of next 7 days) – subgroup of 60 patients 
 
Outcome assessment (Week 5): 
- 
Primary outcome 
 
Outcome assessment (Week 6 – physical visit 3): 
- 
Primary outcome 
- 
All other PROMs 
- 
PPT 
- 
Adverse events 
- 
Return ear EEG device (60 patient subgroup) 
- 
Return left over study medication 
 
Outcome assessment (Week 8 – phone): 
- 
Primary outcome 
- 
ISI 
- 
Adverse events 
- 
Urine test (hCG for pregnancy) – at home 
 
 
4.3 Primary and secondary outcomes 
 
Primary outcome: 
▪ Average back pain intensity during the past 7 days. Difference in change between 
treatment groups (Melatonin vs. placebo) from baseline to 6 weeks. Average pain 
intensity during past 7 days will be assessed on a 0-10 Numeric Rating Scale (NRS) 
(ranging from ‘no pain to ‘worst imaginable pain’).22 The participants will be 
recommended to respond to the question about their average pain intensity during the 
last week at the same time of the day as they will take the study medicine (before 
bedtime). In that way the primary endpoint will be assessed at the same time 
consistently throughout the trial. 
 
Secondary outcomes: 
▪ Trajectory of weekly (at 0, 1, 2, 3, 4, 5 and 6 weeks) NRS back pain intensity scores 
(primary outcome) from baseline to 6 weeks.22Number of patients with more than 30% 
improvement in the primary outcome from baseline to 6 weeks (Number of responders 
are calculated for both the Melatonin and the placebo group). 
▪ Number of patients with more than 50% improvement in the primary outcome from 
baseline to 6 weeks (Number of responders are calculated for both the Melatonin and 
the placebo group). 
▪ Back pain related disability. Difference in change between treatment groups 
(Melatonin vs. placebo) from baseline to 6 weeks. Back pain related disability will be 
assessed using the Roland Morris Disability Questionnaire (RMQ).23,24 RMQ is a 23-
item questionnaire (RMQ) developed to assess functional limitation and disability 
among patients with low back pain. The RMQ 23-item version will be used because 
1) it has been cross-culturally validated in Danish (the original RMQ 24-item version 

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has not), 2) the psychometric properties of the 23 vs 24 item RMQ have been shown 
to be similar.25,26 Each of the 23 items is yes/no (scored as 1 and 0 points respectively) 
with the scale ranging from 0 (no disability) to 23 (extremely severe disability).  
▪ Global Perceived Effect (GPE). Assessment of overall change in back pain from 
baseline to 6 weeks. Participants will be asked at 6 weeks: ‘How is your back pain 
now compared to when you entered this study’, with 5 response options (much worse, 
worse, almost the same/unchanged, improved, much improved).27 
▪ Physical and mental health will be assessed using the Patient-Reported Outcomes 
Measurement Information System (PROMIS-10) Global Health questionnaire version 
1.2.28 Difference in change in physical and mental health scores between treatment 
groups (Melatonin vs. placebo) from baseline to 6 weeks. PROMIS-10 consist of 10 
questions concerning different aspects of global health. The first 9 questions are score 
on a Likert scale with 5 response options, and the last question is asking about pain 
using a 0-10 numeric rating scale. 
▪ Insomnia symptoms. Difference in change between treatment groups (Melatonin vs. 
placebo) from baseline to 6 weeks. Insomnia will be assessed with the Insomnia 
Severity Index (ISI), which is a brief 7 item patient-reported instrument with a score 
ranging from 0-28 (0=best;28=worst), insomnia will be defined according to 
described cut-offs.29,30 
▪ Pain sensitivity (i.e. pressure pain threshold). The primary aim of this trial is to 
investigate if Melatonin is superior compared with placebo in improving patient-
reported pain. To enable us to report the potential effect on similar yet different 
domain of pain (i.e. objectively assessed pain sensitivity), we have included an 
outome measure of pain sensitivity. Difference in change between treatment groups 
(Melatonin vs. placebo) from baseline to 6 weeks. Pressure pain threshold is assessed 
using a handheld algometer.31,32 Pressure pain thresholds will be assessed locally at 
the right erector spinae muscle (3 cm from the fourth lumbar spinous process) and at 
the left upper trapezius muscle (10 cm horizontally from the acromion in direct line 
with the seventh cervical spinous process). 
 
Exploratory outcomes: 
▪ Physiological sleep (subgroup of 60 patients). Difference in change in sleep metrics 
between treatment groups (Melatonin [n=30] vs. placebo [n=30]) from baseline to 4 
weeks. The following sleep metrics will be assessed using ear EEG: sleep period time 
(SPT); time from sleep onset until final awakening (TST); sleep efficiency (SE) which 
is the ratio of TST to time in bed / 100%; sleep onset latency (SOL); wake after sleep 
onset (WASO), wake time within the SPT. The following sleep architecture variables 
will be used: REM sleep latency,  time from sleep onset until first epoch of REM 
stage sleep; amount of wake and stage N1, N2, N3, and R sleep as a percentage of 
SPT; number of awakenings within TST; arousal index which is number of arousals 
per hour. 
 
Data collected during screening: 
▪ Demographic data (sex, smoking, alcohol use, physical activity level, work status, 
civil status, etc.) 
▪ Concomitant medicine use 
▪ Serum levels of ALAT, creatinine, GFR 
▪ Vital signs (Blood pressure, heart rate, weight, height) 
▪ Urine – hCG (i.e. test for pregnancy) 
 

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Table 2: Detailed overview of timing of outcomes and assessments. 
 
 
 
 
Screening 
(Phone) 
 
Eligibility 
assessment 
(Visit 1A) 
 
Ear EEG 
setup 
(Visit 
1B) 
Inclusion &  
baseline 
assessment 
(Visit 2) 
 
 
 
Week 1 
 
 
 
Week 2 
 
 
Week 3 
(Phone) 
 
 
 
Week 4 
 
 
 
Week 5 
 
 
Week 6 
(Visit 3) 
 
 
Week 8 
(Phone) 
Eligibility 
assessment 
X 
X 
 
 
 
 
 
 
 
 
 
Medical 
history 
 
X 
 
 
 
 
 
 
 
 
 
Urine test 
 
X 
 
X 
 
 
X 
 
 
X 
 
Blood test 
 
X 
 
 
 
 
 
 
 
 
 
Informed 
consent 
 
X 
 
X 
 
 
 
 
 
 
 
Vital signs 
including 
weight and 
height 
 
X 
 
X 
 
 
 
 
 
X 
 
NRS pain 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
RMQ 
 
 
 
X 
 
 
 
 
 
X 
 
GPE 
 
 
 
 
 
 
 
 
 
X 
 
ISI 
 
 
 
X 
 
 
X 
 
 
X 
X 
PROMIS-10 
 
 
 
X 
 
 
 
 
 
X 
 
Pain 
sensitivity 
 
 
 
X 
 
 
 
 
 
X 
 
Sleep pattern 
(EEG) 
(60 patients) 
 
X  
X 
X 
 
 
 
X 
 
 
 
Adverse 
events 
 
 
 
X 
 
 
X 
 
 
X 
X 
* The study related examinations and procedure at visit 1 A will only be made if the participants sign the informed consent at the beginning of visit 1A. If the participants 
want to think whether to participate, then the examinations listed at visit 1A will be made at Visit 2.  
 

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4.4 Sample size estimation 
We aim to be able to detect a difference in treatment effect between groups of 1 point on a 0-
10 NRS scale (similar effect as NSAIDs for acute and chronic low back pain).4,33 With 80% 
power and an alpha-level of 0.05 (assuming a SD of 2.5 on the change score), 100 patients 
have to be included in each group when using a t-test for the analysis. The approach to use 
baseline values as covariates instead of change scores implies a further gain in power. Drop 
outs may decrease the power, but due to using a mixed model for analysis, they will still 
contribute information. To take a potential loss in power into account, the sample size is 
increased by 10%, i.e. we aim at a total sample size of 220 patients.  
 
4.5 Measures for reduction in bias 
Participating patients, investigators, outcome assessors and statistical analysts are all blinded 
to treatment allocation. All patient reported data will be filled in by the patient via an online 
questionnaire using REDCap. An assessor blinded to study treatment will perform all 
protocol specific objective outcome assessments at baseline and 6 weeks follow-up. 
Unblinding will first take place after the primary analysis of the data has taken place. 
 A data manager, otherwise, not involved in the study, will prepare the randomization list, 
using a computerized algorithm in REDCap. The randomization list will be sent to Glostrup 
Pharmacy, 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 trial 
medicine will be shipped together with individual code-envelopes for every blinding code to 
the place of trial, and trial site will be responsible for reception control. The code-envelopes 
will be stored at the department of Anesthesiology and Intensive care at Odense university 
hospital (OUH) behind double lock and it can be accessed 24/7.  
Sponsor/PI is not unblinded, except in case of a medical emergency and only if PI/ Sponsor 
finds it necessary to ensure the safety of the subject. The investigator will be able to unblind a 
single participant if medically necessary at all times of the day, without delay or previous 
contact to the sponsor.  A single subject can be unblinded by breaking the code-envelope 
related to the subjects blinding code. If a code-envelope is opened, it is stored in the trial 
master file. 
 
4.6 Description of the study treatment 
After inclusion participants are randomized according to the abovementioned procedure to 
receive either Melatonin (10 mg/day) or placebo for 6 weeks.  
The Glostrup Pharmacy will purchase the active melatonin medicine and manufacture the 
identical appearing placebo tablets. The trial medicine will be labeled with blinding codes 
according to the randomization list by Glostrup Pharmacy. Before dispensing the trial 
medication, the ID-number of the study participant will be written on the medicine cans. The 
trial medicine is to be taken once daily in the evening, 30 min. before going to sleep. 
If a participant experiences an adverse event deemed related to the study 
medication of grade 2 or higher according to CTCAE version 5.0 the dose will be reduced to 
5 mg/day.  
 
4.7 Description of expected time frame for the individual patient 
The time frame for the intervention is 6 weeks, with an end of study follow-up phone call for 
safety at 8 weeks.  
 

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4.8 Rules for termination of the study 
The study will be terminated when all recruited participants have completed their final 
follow-up (last patient – last visit).  The study will be terminated prematurely, if unforeseen 
issues regarding the safety of the study drug should occur. 
 
4.9 Procedures for accounting for the trial medicine, including placebo products 
The study medicine and the placebo tablets will be packaged at Glostrup Pharmacy. The 
study medicine will be delivered together with code-envelopes to the place of the trial (The 
Pain Centre, Odense University Hospital), 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.  
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 6 weeks. Trial 
medication is handed out at baseline (week 0). At the end of the intervention phase, empty 
medicine-cans will be returned, and any non-ingested medicine will be counted by a trained 
employer at the Pain Center OUH. Participants will be asked if they lost any of the tablets. 
Both number of returned tablets and number of lost tablets will be recorded 
To be considered adherend to the protocol it requires at least 80 % adherence to the 
treatment. The study medication and placebo will be counted at study end visit. If the study 
medicine has been reduced during the study period due to adverse events, this will be taken 
into account, when calculating the adherence of the study medication. The remaining study 
medicine and the placebo tablets will be destroyed at the Hospital pharmacy Funen.  
  
4.10 Source data 
Source data that appears from the electronic case report form (E-CRF) are demographic data, 
questionnaire data, concomitant medicine, adverse events (AE) and adverse reactions (AR) 
and data from assessments of Pressure pain thresholds.  
Source data that appears from the patient´s medical record is laboratory data (blood tests). 
Source data from the EEG assessments will be stored in an online Sharepoint folder.  
In case of system break down, all data will be collected in a paper version similar to the E-
CRF version. This data will be entered into the E-CRF as soon as the break down has been 
resolved. Any source data in paper format will be archived in the trial master file. 
 
5. Selection and withdrawal of participants 
5.1 Selection and screening of patients 
Based on the 2021 National Health Profile more than 950.000 people suffer from back pain in 
Denmark,34 and it is the most common reason to visit the general practitioner.35 Therefore, 
we will use a recruitment strategy with advertisements and social media campaigns. We have 
previously used this method with success for recruitment of chronic pain patients in other 
trials.36  Participants that respond to advertisements will receive written information material 
about the trial using E-boks, which is a digital system used for all communication between 
Danish authorities and citizens. They will also be contacted by telephone a few days after 
receiving the written information. During the telephone call additional oral information will 
be given, patients will be able to ask questions and patients will respond to initial screening 

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questions for eligibility. Participants interested in participating in the trial and fulfilling the 
initial eligibility criteria will be invited to a screening interview and eligibility examination at 
the Pain Center at Odense University Hospital (visit 1). Participants fulfilling all eligibility 
criteria and signing informed consent will be invited to an additional visit (visit 2 – Pain 
Center, Odense University Hospital). As eligibility assessment require blood testing with 
some delay in response, the final decision on inclusion of patients will be made at visit 2, 
followed by baseline testing, randomization, and extradition of study medication. In case, 
results from blood samples violate the eligibility criteria, patients will be contacted by phone 
to cancel visit 2 and informing them that they are not eligible for the study.   
 
5.2 Inclusion criteria  
To be eligible for the trial patients must fulfill the following inclusion criteria: 
- 
Age 18 to 64 years 
- 
Understand and write Danish 
- 
Back pain for 3 months or longer 
- 
Back pain must be present on ‘most days’ or ‘every day’ within the past 3 months 
(will be checked by the question: ‘In the past 3 months, how often did you have back 
pain? – response options: ‘never’; ‘some days’; ‘most days’; ‘every day’) 
- 
Back pain must limit life or work activities on ‘some days’, ‘most days’, or ‘every 
day’ within the past 3 months. (will be checked by the question: ‘In the past 3 months, 
how often did your back pain limit your life or work activities? – response options: 
‘never’; ‘some days’; ‘most days’; ‘every day’) 
- 
Average pain intensity of 4 on 0-10 Numeric Rating Scale [NRS] in the past 7 days 
(ranging from ‘no pain’ to ‘worst imaginable pain’). 
- 
All fertile women must use safe contraception (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 contraception. 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 (reported by the participant). 
 
5.3 Exclusion criteria 
Patients be excluded based on the following exclusion criteria: 
- 
Known abuse of alcohol or other substances 
- 
Self-selected non-user of e-boks 
- 
Opioid use (reported by participant) 
- 
Known malignancies within past 6 months (reported by participant) 
- 
Known fractures within past 4 months (reported by participant) 
- 
Known lumbar radiculopathy (reported by participant) 
- 
Known spinal stenosis (reported by participant) 
- 
psychiatric disorders and/or psychotic symptoms evaluated by the investigator 
(reported by participant) 
- 
Suicide and self-damage thoughts (reported by participant) 
- 
Inflammatory/autoimmune arthritis (reported by participant) 
- 
For the EEG subgroup:  
o If the anatomy of the outer ear making it impossible to do ear EEG monitoring  
o If there have a perforation of the tympanic membrane (eardrum)  
o If they have an ear tube in the tympanic membrane   

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o If their ear piercings that are not compatible with ear EEG. 
o If they use anticoagulants 
 
- 
Patients with contraindications to Melatonin according to the Danish Medicines 
Agencys approved product information: 
▪ Moderate to severe kidney insufficiency (GFR < 30 mL/min) 
▪ Moderate to severe liver insufficiency (ALAT must not be elevated 
more than 3-fold over highest reference level) 
▪ Auto-immune diseases 
▪ Epilepsy 
▪ Warfarin use 
▪ Benzodiazipin use (including hypnotics) 
▪ Fluvoxamin use (Ciprofloxacin, Norfloxacin) 
▪ Calcium antagonist use (Verapamil, Nifedepin) 
▪ Pregnancy or pregnancy-wish or breastfeeding (a negative pregnancy 
test has to be available for all fertile female patients at baseline) 
▪ Intolerance to melatonin 
 
5.4 Procedures for withdrawal 
A participant will be withdrawn from the study medication:  
1) In case of a 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) If the participant during the trials wants to cease the treatment, the participant is 
withdrawn from the study medication. 
3) If the participant during the trial wants withdraw from the study, the participant is 
withdrawn from the study and will not be contacted for further assessments. 
 
All participants that are withdrawn from the study medication will be encouraged to complete 
all visits as scheduled. Prematurely discontinued participants will be followed up weekly by 
telephone until any adverse events have ceased or are stable. Participants that are withdrawn 
from the treatment will not be replaced, and will be included in the intention-to-treat 
population. According to our sample size calculation, we will include participants enough to 
tolerate a drop-out rate of up to 20%. Both intention-to-treat and per protocol analysis will be 
performed and compared to assess the robustness of the primary analysis. 
If changes in the patient’s other pain medication occur during the trial, this will be considered 
a protocol violation, and the participant will not be included in the Per Protocol Population.  
6. Patient treatment 
 
6.1 Detailed description of the study treatment 
The planned trial period with study treatment is scheduled to 6 weeks (42 days). Patients will 
receive either 10 mg Melatonin (2 x 5 mg tablets) or placebo (2 tablets looking identical to 
the study medication) to be taken once daily approximately 30 min before bedtime during all 
days in the study period. The study medication is not to be taken within 2 hours of a meal. 
 
To take into account that the final follow-up visit (visit 3) may not be possible to schedule for 
all patients at day 42 and that the effect of Melatonin is transient, all study participants will 
receive 100 tables of the study medication (Melatonin or placebo) corresponding to 50 days 

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of treatments. Patients will be instructed to continue treatment until the end of trial visit (visit 
3). 
 
If a participant experiences an adverse event deemed related to the study medication of grade 
2 or higher according to CTCAE version 5.0 the dose will be reduced to 5 mg/day.  
 
 
Special considerations in relation to intake of study medication to convey to patients: 
- 
NSAIDs should not be used by study participants in the evening (may reduce the level 
of endogenous melatonin) 
- 
Betablockers should be used in the morning as it may suppress endogenous melatonin 
- 
Individuals with impaired glucose tolerance or diabetes should not take the study 
medication within 3 hours of a meal (instead of 2 hours) 
 
 
6.2 Off label use 
Melatonin is primarily marketed for sleep disorders and jetlag. In many countries Melatonin 
is an over-the-counter drug, but require prescription in Denmark. In Denmark, the indications 
for prescription are: 1) short term treatment of insomnia/poor sleep quality in patients older 
than 55 years; 2) short term treatment of jetlag in adults; and 3) insomnia in 
children/adolescents with autism and/or Smith-Magenis syndrome.19  
 
In this trial the use of melatonin will be ‘off label use’ to treat pain in patients with chronic 
back pain. 
 
6.4 Rules for concomitant medication/treatment during the trial 
In the trial we will allow continued, but not new co-interventions (e.g. pain medication 
use, exercise therapy, manual treatment etc.). This will be monitored by the shared electronic 
medications record and by questionnaire. 
 
6.5 Measures to promote compliance 
Participants will receive a weekly 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 patients after termination of the study 
Treatment of patients will terminate after 6 weeks (visit 3), there will be no additional treatment 
with the study medication after the 6 weeks (visit 3). As recruitment is conducted through open 
sources (i.e. social media and advertisements) and not through a clinical pathway patients that 
still have back pain after the study period will be recommended to contact their own general 
practitioner. The general practitioner will then facilitate treatment according to general 
guidelines and standard procedures for treatment of patients with back pain in primary care. 
 
7. Outcomes 
 
7.1 Study outcome measures 
For a detailed description of the study outcomes please refer to section 4.3 
 
Primary outcome: 

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- 
Pain intensity - NRS pain (average in the past 7 days) 
 
Secondary outcomes: 
- 
Back pain related disability - Roland Morris Disability Questionnaire (RMQ) 
- 
Global Perceived Effect (GPE) 
- 
Physical and mental health - Patient-Reported Outcomes Measurement Information 
System (PROMIS-10) Global Health questionnaire v. 1.2. 
- 
Insomnia symptoms – Insomnia Severity Index (ISI) 
- 
Pain sensitivity –pressure pain threshold (PPT) 
 
Exploratory outcomes: 
- 
Physiological sleep metrics – ear EEG 
 
7.2 Description of specific assessment procedures 
7.2.1 Patient-reported outcomes: 
All patient-reported outcomes will be collected using an online questionnaire administered 
through REDCap, which ensure data logging and comply with all demands from the Danish 
Data Protection Agency regarding data security. For timing of collection of patient-reported 
outcomes please refer to section 4.3. 
 
7.2.2 Pressure pain thresholds (PPT) 
PPTs are assessed using a handheld algometer.31,32 Handheld pressure algometry with a 
manually applied standardized pressure stimulation to assess pain sensitivity of deep 
structures is a reliable method that is extensively used and validated32,37. PPTs will be 
assessed locally at the right erector spinae muscle (3 cm from the fourth lumbar spinous 
rocess) and at the left upper trapezius muscle (10 cm horizontally from the acromion in direct 
line with the seventh cervical spinous  process) using a handheld pressure algometer 
(Somedic Sales AB, Norra Mellby, Sweden) with a stimulation area of 1 cm2, and a pressure 
rate of 30 kPa/s. Patients are instructed to press a button when the pressure is perceived as the 
first sensation of minimal pain. Two assessments with 20-second intervals between 
assessments are completed for each site and the average at each site is used for analysis. For 
timing of assessment of PPT please refer to section 4.3. 
 
7.2.3 Physiological sleep metrics (subgroup of 60 patients) 
After recruitment of the first 100 patients, 60 patients will be selected for objective 
assessment of sleep. Before inclusion of the first patient in this sub-study we will notify 
VMK about the ear EEG sub-study, which is a clinical investigation of medical devices under 
MDR article 82. This sub-study application is expected to be submitted to VMK in 2025, 
when it has been finally clarified whether the ear-EEG equipment that will be used in the sub-
study has achieved CE marking or not. Assessment of changes in sleep metrics will be 
performed during two 5 of 7-day periods. One period at baseline prior to initiation of study 
treatment (between visit 1B and visit 2) and one period in week 4. The assessment will be 
performed using an ear-EEG research solution (T&W Engineering A/S, Lynge, Denmark) 
that is custom-fitted for each individual patient. The Recorder and headset are both a low-risk 
class I medical device in EU. T&W Engineering provides and supports the solution 
throughout the study period, including ongoing firmware updates to ensure data quality. 
Components that break during the study will be replaced. All Recorders and Headsets will be 
returned to T&W Engineering when they are no longer needed, breaks, or need firmware 
update. Prior to the actual assessment each individual patient will have a custom-fit earplug 

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moulded, which will hold the EEG electrodes. Furthermore, patients will be instructed in the 
use of the system. Previous studies have demonstrated the feasibility of measuring ear EEG 
in patients own home and shown that ear-EEG compares to conventional scalp-EEG (i.e. 
used in polysomnography assessment of sleep) with similar performance.38,39 Sleep variables 
will be derived from the EEG assessments as recommended by the American Academy of 
Sleep Medicine (AASM).40 The intended purpose of the ear-EEG solution is to acquire, 
record, and transmit electrical brain activity (EEG) of patients 18 years and older. The 
solution is composed of a Recorder and a Headset. The Recorder is a battery-powered 
logging device for multiple use. The Headset is an electrode array intended for single patient 
- multiple use, to acquire electrical activity of the brain (EEG) using the Recorder. The 
Headset is composed of two customized earpieces each containing 3 embedded dry 
electrodes. The electrodes are placed inside the ear canal and in the concha of the ear. All 
investigators will be trained in the use of the ear-EEG solution prior to initiation of the study. 
This includes customization of ear pieces, mounting of earpieces, and setting up and 
downloading data from the ear-EEG solution. The earpieces are labelled with lot/serial 
numbers for subsequent tracing and identification. At the site, a device accountability system 
will be maintained during the study and afterwards, documenting device shipment and 
receipt, storage at the site, use, and return as applicable. Detailed information about the 
investigational solution can be found in the Investigator’s Brochure. See Table 2 for an 
overview of the manufacturing process and responsibility. 
 
Table 3 Manufacturing of ear-EEG solution 
Step 
Process description  
Responsible 
1 
Impression of the subjects’ ears and measuring 
of the length of the subject’s neck size 
Odense University Hospital 
1 
Production of Recorder and individualized 
Headsets  
T&W Engineering A/S  
 
Study procedures related to ear EEG: 
(Physical visit 1A): Ear measurement for individual molding of ear electroencephalography 
(EEG) research solution: 
- 
Ear impression for individualization of the Headset. Ear measurement is performed by 
a trained person (medical doctor or study nurse) on site. From the impression, 
personal earbuds to the Headsets are produced. 
 
Ear EEG setup (physical visit 1B): 
- 
Instructions and handing out ear-EEG solution to patients. Once the Headsets are 
ready a visual inspection is performed to assess the quality of the earbud fit. This is 
done using a short recording and manual inspection of the recorded data in term of 50 
Hz line noise contamination. The presence of large amounts of 50 Hz noise indicates 
that the electrodes has insufficient contact to the skin. An EEG channel is accepted, 
meaning that the underlying electrodes are considered to have a good connection to 
the skin, when the neural component, being dominated by frequencies well below 50 
Hz, is clearly visible in the data trace. If not at least 2 channels in each ear have good 
connections after repeated cleaning of the skin, the study participant is withdrawn. 
Additionally, the participant’s capability of mounting the earpieces autonomously and 
uploading data to the external device will be assessed. Furthermore, a training session 
of completing sleep diary, pain questions and ease-of-use and comfort questionnaire 
will be completed. 

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Getting accustomed to repeated ear EEG use (Between visit 1B and visit 2 – home) 
- 
Start 5-day adaption period for sleeping with ear EEG (2 days with; 1 day without; 2 
days with). The participant will be sent home with the equipment and asked to sleep 
with it on the following 2 nights, followed by one night without the device followed 
by another 2 nights sleeping with the device. This phase is to allow the participant to 
get accustomed to wearing the device during several nights. The participants are also 
asked to upload the recorded data each morning to the cloud and recharge the 
Recorder. 
 
Pre-intervention Ear EEG assessment (Between visit 1B and visit 2 – home) 
- 
After 5-day adaptation period – First week of EEG sleep assessment (5 out of next 7 
days). The participant will be asked to sleep with the ear-EEG device for 5 nights in 
the following week. Participants are encouraged to maintain normal sleeping habits. 
The participant will upload recordings to provided PC every day. In case of low 
compliance with EEG recordings or data upload the investigators will contact the 
participant, clarify and provide necessary support. 
 
During-intervention Ear EEG assessment (Week 4 – home) 
- 
The participant will be asked to sleep with the ear-EEG device for 5 nights during this 
week. Participants are encouraged to maintain normal sleeping habits. The participant 
will upload recordings to provided PC every day. In case of low compliance with 
EEG recordings or data upload the investigators will contact the participant, clarify 
and provide necessary support. 
 
Return ear EEG solution (Week 6 – physical visit 3): 
- 
Return ear EEG solution. The participant return to the study site for an end of study 
visit to return the ear-EEG solution. 
- 
Registration of adverse device events, debriefing and completion of the Summative. 
The PI will explore and register any adverse device events, and ease-of-use and 
comfort using Ease-of-use and Comfort questionnaire and System Usability Scale. 
 
8.0 Safety evaluation 
 
8.1 Specification and justification of safety parameters 
As described in section 2.4 Melatonin is considered safe to use and the risk of serious adverse 
drug reactions is considered to be low. Liver function and kidney function is assessed before 
inclusion measuring Serum levels of ALAT, Creatinine and GFR. Urine-hCG is measured with 
a sensitivity of minimum 25 mIU/ml before inclusion and after 3 and 6 weeks in all fertile 
women. At week 3, 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.  

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• 
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.  
• 
Suspected unexpected serious adverse reactions (SUSAR): an adverse reaction that is 
both unexpected and serious. 
AE, AR, SAE, and SAR are registered after 3, 6 and 8 weeks directly in REDCap/eCRF. See 
more specifically 8.5. The SmPC for Melatonin (see section 2.4) 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 Monitoring of patients in case of adverse events/adverse reactions  
Patients are offered follow up at the Pain Center at Odense University Hospital by the primary 
investigator until adverse events/adverse reactions have ceased or are stable. 
 
8.5 Reporting of serious adverse events and unexpected serious adverse events  
If an AE is considered serious, based on the criteria above, it will qualify as an SAE. The 
investigator will report all SAE’s to sponsor immediately but no later than 24 hours after the 
event. All SAE’s are registered in REDCap, so the Sponsor automatically get a notification 
when a SAE is reported in REDCap. In the REDCap the investigator will also report 
suspected causality. 
All SAE’s judged by the investigator and/or the sponsor as having a reasonable suspected 
causal relationship to an investigational medicinal product qualify as a SAR. 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, it will be considered a SUSAR. 
In this case, sponsor will unblind the subject and immediately contact the GCP unit for 
reporting the SUSAR in EudraVigilance.We have a collaboration with the GCP Unit at 
Odense University Hospital, and they will assist us with the reporting in the EudraVigilance 
system. 
All relevant information about a SUSAR, which is fatal or life-threatening, will be reported in 
EudraVigilance as soon as possible, and no later than 7 days after the sponsor is made aware. 
No later than 8 days after the first report, relevant information about the sponsors and 
investigators follow-up to the report must be entered in EudraVigilance. Any other SUSAR 
will be reported in EudraVigilance no later than 15 days from the time the sponsor is made 
aware. All reports must be accompanied by comments on possible consequences for the trial. 

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Once a year throughout the duration of the clinical trial, the sponsor will provide a list of any 
SARs and a safety report to the authorities via CTIS. 
No more than 15 days after completion of a trial, the sponsor will report in CTIS that the trial 
has been completed. As soon as possible and no later than one year after the trial has ended, 
the trial results and a safety report will be reported in CTIS.   
In case of a SUSAR unblinding will happen in accordance with the unblinding procedure 
mentioned at section 4.5.  
9.0 Statistics 
 
9.1 Statistical methods 
Difference in change from baseline to 6 weeks in the primary outcome (mean NRS pain in 
past 7 days, continuous) between the intervention and the placebo-control group will be 
estimated using a mixed linear model approach with  time (baseline, 1, 2, 3, 4, 5 and 6 
weeks), treatment arm (Melatonin or placebo) and the interaction between time and treatment 
arm, as fixed effects and intercept and slope as patient-specific random effects (NRS baseline 
value will be considered a covariate in the model). Difference in change in secondary 
outcomes from baseline to 6 between the intervention and the placebo-control group will also 
be estimated using a mixed linear model approach with the respective secondary outcome, 
time (baseline, 3, and 6 weeks), treatment arm (Melatonin or placebo), the interaction 
between time and treatment arm as fixed effects and intercept and slope as patient-specific 
random effects( the respective secondary outcome value at baseline will be considered a 
covariate in each of the models).  The error variance will be allowed to vary over time and 
across the two arms, except at baseline. The variance-covariance matrix of the random effects 
will be allowed to vary across the two arms. Interactions will be parametrized as time 
dependent treatment effects such that the treatment effect at week 6 corresponds directly with 
the efficacy parameter of interest. The treatment effect at baseline will be set to 0 to reflect 
randomization. The treatment effect will be expressed as the gain in reduction observed in the 
intervention arm, i.e. a positive number expresses a favoring of the intervention. The 
prespecified efficacy analyses will be based on the intention-to-treat (ITT) principle, which 
includes all participants that are assessed and randomized at baseline. In the case of missing 
data during the 6-week trial, repeated measures linear mixed models will take this into 
account automatically, under the assumption that data is missing at random.  
 
Fitting of the mixed models will be based on the restricted maximum likelihood technique. In 
case of convergence problems, the model will be simplified by additional restrictions on the 
variance parameters with respect to equality over time and between the two arms. 
 
Sensitivity analyses with respect to the missing at random assumption will be conducted.  
These analyses will be based on multiple imputation and follow to approaches. First, we will 
consider a tipping approaches adding to all generated outcome values a constant value delta, 
mimicking the expectation that missing outcomes values are in reality higher than those we 
would expect under MAR. The second approach focus on patients in the intervention arm, 
who stop participation in the trial, i.e. for whom both the outcome values as well as 
information on the medication is missing after the finally observed outcome. In these patients 
there is a risk that these patients have stopped the treatment and hence that they start to 
become comparable to the placebo arm. To address this, in these patients the further 
increments are generated using the distribution of the increments observed in the placebo arm 

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in patients with similar values until drop out. Details of these analyses will be fixed in the 
statistical analysis plan.  
 
With respect to potential non-compliance, also a per-protocol analysis will be performed, 
with a per protocol population defined as patients with an adherence to the treatment of at 
least 80%. 
 
At the end of the intervention phase, empty medicine-cans will be returned and any non-
ingested medicine will be counted by a trained employer at the Pain Center OUH. 
Participants will be asked if they lost any of the tablets. Both number of returned tablets and 
number of lost tablets will be recorded 
It is required for the participants to have an adherence of the active medication and placebo of 
at least 80 % during the study period to be defined as ‘compliant’. The study medication and 
placebo will be counted at the study end visit.  
 
In two separate responder analysis, a responder is defined as a patient who report more than 
30% and 50% decrease in pain after 6 weeks, respectively. Treatment differences between 
treatment arms will be expressed by adjusted odds ratios. These will be based on a logistic 
regression model including  the baseline pain intensity value as covariate.  
 
A detailed statistical analysis plan (SAP) will be made publicly available before the statistical 
analysis is initiated. The SAP will include a detailed plan of the analysis of all secondary 
outcomes. 
 
9.2 Trial interpretation 
 
Please refer to table 4 for a detailed overview of the trial interpretation for all possible effect 
estimates and 95% CI scenarios. A difference of 1 point in the primary outcome is considered 
clinically relevant.  
 
Table 4 Trial interpretation for different estimate and 95% CI scenarios. 
Scenario 
Estimate 
Lower bound 
CI 
Upper Bound 
CI 
 
1. 
>=1  
>=1  
 
We have demonstrated 
an intervention effect of 
clinically relevant 
magnitude  
2. 
>=1  
>=0, <=1   
 
We have demonstrated 
an intervention effect 
and obtained a positive 
intervention effect 
estimate of clinically 
relevant magnitude. 
3. 
>=1  
<=0  
 
We obtained a positive 
intervention effect 
estimate of clinically 
relevant magnitude, but 
we could not 
demonstrate an 
intervention effect  

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4. 
>=0,<=1 
>=0 
>=1 
We have demonstrated 
an intervention effect 
and obtained a positive 
intervention effect 
estimate. 
5. 
>=0, <=1 
>=0  
<=1  
We have demonstrated 
an intervention effect 
but also the absence of 
an intervention effect of 
clinically relevant 
magnitude.  
6. 
>=0, <=1 
<=0  
>=1 
We obtained a positive 
intervention effect 
estimate, but we could 
not demonstrate an 
intervention effect  
7 
>=0,<=1 
<=0  
<=1 
We obtained a positive 
effect estimate but also 
demonstrated the 
absence of an 
intervention effect of 
clinically relevant 
magnitude. 
8. 
<=0  
 
>=1 
We obtained a negative 
intervention effect 
estimate, but we could 
not exclude that the 
intervention effect is of 
clinically relevant 
magnitude.  
9. 
<=0  
 
>=0, <=1  
We obtained a negative 
intervention effect 
estimate and 
demonstrated the 
absence of an 
intervention effect of 
clinically relevant 
magnitude.  
10. 
<=0  
 
<=0  
We have demonstrated 
the absence of a positive 
intervention effect  
 
 
10. Direct access to source data/source documents 
 
According to the Danish executive order on GCP, informed consent from patients will also 
include consent to monitoring, auditing and/or inspection. The investigators are authorized to 
direct access to source data/documents (including patient’s files) in connection with 

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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 
 
 
The GCP unit at OUH will be responsible for monitoring the study in accordance with the ICH 
GCP guidelines. Data processing regarding the trial will be reported to the list of on-going 
research projects via the Executive Secretariat at OUH. Confirmation that standard procedures 
for quality control and quality assurance will be complied with, cf. ICH GCP guidelines. 
 
12. Ethics 
 
12.1 Ethical considerations 
 
The trial is initiated by the investigators. Neither investigators nor patients have any economic 
interests in the trial.  
 
Half of the patients will receive active treatment with Melatonin and the other half of patients 
will receive placebo. A parallel group design was chosen to reduce bias and secure a trial with 
good internal validity (i.e. scientific credibility).  
 
There are some risk of having side effects from the study medication. The risk of serious 
adverse reactions from treatment with Melatonin is low. Side effects expected most likely to 
occur are: Headache and somnolence (i.e. ‘common’ side effects according to SmPC).  
 
Potential benefits for patients are that they may experience reduced pain-intensity (and 
improved sleep for those patients with insomnia symptoms). The results from the study will 
potentially be of benefit for other patients with chronic back pain.  
 
12.2 Recruitment, information and collection of informed consent 
Participants for the trial will be recruited through advertisements and social media campaigns.  
Written information will be send via e-boks to interested patients and be contacted by telephone 
a few days after receiving the written information. During the telephone call additional oral 
information will be given, patients will be able to ask questions and patients will respond to 
initial screening questions for eligibility. It is emphasized that participation is voluntary, and 
that consent can be withdrawn at any time. 
 
Participants interested in participating in the trial and fulfilling the initial eligibility criteria will 
be invited to a screening interview and further eligibility examination at the Pain Center at 
Odense University Hospital (visit 1A). This visit will be at least 24 hours after the screening 
and study information over the phone. Participants are welcome to bring a lay 
representative/companion at visit 1A. Before informed consent is collected further oral 
information about the trial is repeated at visit 1A. It is secured that the information can be given 
in privacy. 
 

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For all patients, oral information will be given by telephone by a study 
nurse/coordinator/medical student. But a doctor will make the last evaluation of the 
inclusion/exclusion criteria, and it will also be a doctor who give a detailed information about 
the study and that collects the informed consent.  
 
13. Handling and filing of data and biological material 
13.1 Handling of data 
The handling of data will comply with Regulation 2016/679 of the European Parliament and 
of the Council of 27 April 2016 on the protection of natural persons with regard to the 
processing of personal data and on the free movement of such data (GDPR) and with the 
Danish Data Protection Act. 
Data obtained from the participant’s medical file will be data about concomitant medication 
from the shared medication record and laboratory data (blood tests). No data will be obtained 
from the participants file, before informed consent is given. 
Ear-EEG data will be uploaded directly from participants and stored on secured servers at 
Aarhus University. Data exchange with collaborators will happen through a secure data sharing 
service. EEG data will be saved pseudo-anonymized in a data system at Aarhus University to 
which relevant personnel at the site will have access. Data will be uploaded and transferred to 
the designated data system directly by the participant on daily basis. 
Questionnaire data are collected online using RedCap and entered by the patients. 
 
All other data are entered into the eCRF in RedCap by the primary investigator, the sub 
investigator or the study nurse.    
 
5 year after termination of the study, the data will be anonymized.  
 
13.2 Handling of biological material 
 
At baseline, blood will be collected for the assessment of liver and kidney function. The 
blood samples will be analysed at the Department of Clinical Biochemistry at Odense 
University Hospital, and will be destroyed after analysis. No blood samples will be stored or 
sent abroad. The samples are processed in compliance with GDPR and the Danish Data 
protection Act. 
 
14. Financing and insurances 
14.1 Insurance 
Participating patients are covered by the governmental patient insurance, which includes all 
patients in the Danish health care system. 
 
14.2 Financing 
The study is funded by a grant from Sygesikringen ‘danmark’ (Health Insurance Denmark): 
 
Salary: 
Salary for Prof. Preben Kidmose (responsible for ear EEG) 
35,500 DKK 
Salary PhD-student Kübra Kilic 
 
                      1,469,000 DKK 
Salary Postdoc (analysis of ear EEG) 
                                            138,500 DKK 
Salary PI/Sponsor (MD Karin Due Bruun) 
 
 190,226 DKK 

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Salary Project MD 
 
 
 
 369,000 DKK 
Salary Statistician 
 
 
                       29,000 DKK 
 
Total salary  
 
 
                       2,231,226 DKK 
 
 
 
 
 
Operating expenses: 
Transport compensation for patients 
                                             41,280 DKK 
Trial medication 
 
 
                       209,950 DKK 
GCP monitoring 
 
 
 
 35,000 DKK 
blood tests, pregnancy tests etc. 
 
   
 108,000 DKK 
Ear EEG 
  
 
                                             240,000 DKK 
Conference PhD-student  
 
                       10,000 DKK 
 
Total operating expences  
 
                      644,230 DKK 
 
Total budget   
 
 
 
 
 
 
                                                                  2,875,456 DKK 
 
The funder (Sygesikringen ‘danmark’) have no role in the design, conduct or dissemination of 
the trial. 
 
14.3 Compensation for patients 
Patients that reside more than 25 kilometers away from the place of the trial, will receive 
compensation for expenses for transportation. The compensation fee is 2.19 DKK 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). 
The primary report of 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 on the primary report will be PhD-student Kubra Kilic.  
Last author on the primary report will be Prof. Jonas Bloch Thorlund. 
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. 
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