Occipital Nerve Stimulation in Medically Intractable Chronic Cluster Headache
Phase: PHASE3
Conditions: Chronic Cluster Headache
Sponsor: Leiden University Medical Center

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
1
Protocol 
 
Occipital nerve stimulation in medically 
intractable, chronic cluster headache 
 
 
 
 
Investigator and contact person                               
 
Patty GG Doesborg, MD 
Department of Neurology, K5-104 
Leiden University Medical Centre 
Leiden, the Netherlands 
Telephone: +31-(0)71-5261645 
Email: p.g.g.doesborg@lumc.nl 
 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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Department of Neurology, LUMC, Leiden, The Netherlands: 
Prof. Michel D. Ferrari, MD PhD (principal investigator) 
Joost Haan, MD PhD 
Poldi LA Wilbrink, MD (previous investigator) 
Ilse F de Coo, MD (previous investigator) 
 
Department of Neurosurgery, MUMC+, Maastricht and Department of Neurosurgery, Atrium MC, 
Heerlen, The Netherlands: 
Onno Teernstra, MD PhD 
Geert Spincemaille, MD PhD  
 
Department of Anesthesiology, Erasmus MC, Rotterdam, The Netherlands 
Prof. Frank.J.P.M. Huygen, MD PhD 
 
Department of Biomedical signals and systems University of Twente, Enschede, The Netherlands 
Prof. Peter.H. Veltink, PhD 
 
Department of Neurology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands 
Wim.M. Mulleners, MD PhD 
 
Department of Neurosurgery, Radboud MC, Nijmegen, The Netherlands 
Robert van Dongen, MD PhD 
 
Department of Neurology, Boerhaave MC, Amsterdam, The Netherlands 
Emile Couturier, MD 
 
Department of Neurology, Zuyderland hospital, Heerlen, The Netherlands 
Peter J. Koehler, MD PhD 
 
Department of Anesthesiology, Diakonessenhuis, Zeist,The Netherlands 
Frank Wille, MD PhD 
 
Department of Anesthesiology, Alrijne Hospital, Leiderdorp,The Netherlands 
Katja Burger, MD PhD 
 
Department of Neurology, CHR Citadelle, Liege, Belgium,  
Prof. Jean Schoenen, MD PhD 
Delphine Magis, MD, PhD 
 
Department of Neurosurgery, CHR Citadelle, Liege, Belgium 
Frédéric Belle, MD 
 
Department of Neurology, Royal Free Hospital, London, UK 
Prof. Peter J. Goadsby, MD, PhD 
 
Department of Neurology, National Institute of Neuroscience,  Budapest, Hungary 
Judit Àfra, MD, PhD 
 
Department of Neurosurgery, National Institute of Neuroscience, Budapest, Hungary 
Lorand G. Erőss, MD, PhD 
 
 
Department of Neurology, Schmertz klinik, Kiel, Germany 
Prof. Hartmut Göbel, MD, PhD 
 
Department of Neurosurgery, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany 
Prof. Volker Tronnier, MD, PhD 
 
Department of Medical Statistics & BioInformatics, LUMC, Leiden, The Netherlands: 
 
Prof. Ronald Brand, PhD  
Erik v Zwet, PhD 
 
 
Department of Health Services Research, Maastricht University, Maastricht, The Netherlands 
Prof. S. Evers, PhD 
 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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Funding:  
 
Medtronic, Unrestricted grant 
Non voting representative Department of Benelux and Nordic Region, Medtronic, Heerlen 
Rik.P.J. Buschman, Phd 
 
Ohra Nuts 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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Table of Contents 
 
1. 
Summary ............................................................................................................... 6 
2. 
Background ........................................................................................................... 7 
2.1 Cluster headache ................................................................................................. 7 
2.2 Treatment ............................................................................................................. 7 
2.3 Social and economic impact ................................................................................ 7 
2.4 Hypothalamic deep brain stimulation .................................................................. 8 
2.5 Stimulation of the suboccipital nerve in CH ........................................................ 8 
3. 
Study Rationale ..................................................................................................... 9 
4. 
Study design ........................................................................................................ 10 
5. Patient recruitment .................................................................................................. 16 
6. Study Purpose .......................................................................................................... 16 
Objectives ................................................................................................................. 16 
7. Endpoints ................................................................................................................. 16 
7.1 Primary .............................................................................................................. 16 
7.2 Secondary ........................................................................................................... 16 
8. Patient Selection Criteria ........................................................................................ 18 
8.1 Inclusion Criteria ............................................................................................... 18 
8.2 Exclusion Criteria .............................................................................................. 20 
9. Protocol Description ................................................................................................ 21 
9.1 Detailed research plan ....................................................................................... 21 
9.2 Schedule ............................................................................................................. 22 
9.3 Interview by telephone ....................................................................................... 23 
9.4 Data.................................................................................................................... 23 
9.5 Stimulation parameters ...................................................................................... 23 
9.6 Surgery and hospital visits ................................................................................. 23 
10. Methods .................................................................................................................. 25 
10.1 Defining stimulation amplitudes ...................................................................... 25 
10.2 Surgery ............................................................................................................. 26 
10.3 Devices used..................................................................................................... 27 
11. Economic evaluation .............................................................................................. 28 
11.1 Design and participants ................................................................................... 28 
11.2 Measurement .................................................................................................... 29 
11.3 Analysis ............................................................................................................ 30 
11.4 Cost-of-illness (COI) ........................................................................................ 32 
12. Protocol deviations ................................................................................................ 32 
13. Safety monitoring ................................................................................................... 33 
13.1 Adverse Event Definitions ................................................................................ 33 
13.2 Adverse Event (AE): ......................................................................................... 33 
13.3 Adverse Device Effect (ADE): ......................................................................... 33 
13.4 Serious Adverse Event (SAE): .......................................................................... 33 
13.5 Serious Adverse Device Effect (SADE): .......................................................... 34 
13.6 Recording and reporting of AEs and device events ......................................... 34 
13.7 Adverse Event review process .......................................................................... 35 
13.8 Outcome ........................................................................................................... 35 
13.9 Follow-up of Adverse Events ........................................................................... 36 
13.10 Patient Death ................................................................................................. 36 
14. Study Termination .................................................................................................. 37 
15. Administrative Procedures..................................................................................... 37 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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15.1 Regulatory and ethical considerations ............................................................ 37 
15.2 Informed Consent ............................................................................................. 37 
15.3 Ethics Committee Requirements ...................................................................... 38 
15.4 End of the Study ............................................................................................... 38 
15.5 Patient confidentiality ...................................................................................... 38 
16. Statistical methods ................................................................................................. 39 
16.1 The aim of the study ......................................................................................... 39 
16.2 Endpoints ......................................................................................................... 39 
16.3 Multi testing correction.................................................................................... 40 
16.4 Power and sample size ..................................................................................... 41 
16.5 Analyses ........................................................................................................... 42 
     16.6 Randomisation and blinding                                                                            39  
17. Risk assessment ...................................................................................................... 44 
18. Investigator / Site Selection ................................................................................... 44 
18.1 Implantation site .............................................................................................. 44 
18.2 Patient recruitment site .................................................................................... 45 
18.3 Training requirements ..................................................................................... 45 
19. Study Organization ................................................................................................ 45 
19.1 Principal Investigator ...................................................................................... 46 
19.2 Coordinating Clinical Investigator .................................................................. 46 
19.3 Amendment Procedure ..................................................................................... 46 
19.4 Boards .............................................................................................................. 46 
20. Ethical Basis .......................................................................................................... 47 
21. Insurance / Indemnification ................................................................................... 48 
22. Publication Policy .................................................................................................. 48 
23. Study reimbursement .............................................................................................. 49 
24. Appendices ............................................................................................................. 49 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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1. Summary 
Cluster headache (CH) is a primary headache disorder characterized by recurrent 
short-lasting attacks (15 to 180 minutes) of excruciating unilateral periorbital pain 
accompanied by ipsilateral cranial autonomic signs (1). The 1-year prevalence of CH 
is about 0.1 %, the male: female ratio is 3:1. The majority of patients have cluster 
periods of weeks to months with frequent attacks which are alternated with symptom-
free periods of months to several years; the episodic from of CH. In about 10% of 
patients the CH is chronic (CCH) in which either no remission occurs within 1 year or 
the remissions last less than 1 month. At least 10 % of CCH patients are refractory to 
medical treatment or cannot tolerate the treatments (2).  
 
Recent pilot studies suggest that occipital nerve stimulation (ONS) in medically 
intractable CCH (MICCH) might offer an effective alternative to medical treatment. 
There are no randomised clinical trials and a placebo effect cannot be excluded. Long 
term tolerability is known from other indications. 
 
Here we propose a prospective, randomised, double blind, parallel group multi-centre 
international clinical study to compare the reduction in attack frequency from baseline 
of occipital nerve stimulation (ONS) in patients with MICCH between two different 
stimulation conditions: high (100%) and low (30%) stimulation. 
 
Following implantation there will first be a run-in phase of 10 days of 10% 
stimulation intensity, followed by a stepwise monthly increase up to either 30% or 
100%. Patients will be assessed monthly by a blinded assessor. The primary outcome 
measure is the mean number of attacks over the last 4 weeks of the double blind 6 
month treatment period in the 100% versus the 30% treatment group. Hereafter, in an 
open extension phase of 6 months, all patients will receive 100% stimulation or the 
stimulation considered optimal by the patient. 
 
Secondary outcome measures include the rate of responders (≥ 50% reduction in 
attack frequency during the last 4 weeks of each treatment period), patient’s 
satisfaction, medication use, quality of life, mean pain intensity, economic evaluation 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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and whether patients would recommend the treatment to another patient. We will also 
investigate whether predictive factors can be identified for efficacy.  
 
2. Background 
2.1 Cluster headache 
Trigeminal autonomic cephalalgias (TACs) are characterized by frequent, short-
lasting attacks of unilateral extremely severe headaches accompanied by ipsilateral 
facial autonomic features and are the most severe of the primary headache disorders 
(1). TACs include cluster headache (CH), paroxysmal hemicrania (PH) and short-
lasting unilateral neuralgiform headache with conjunctival injection and tearing 
(SUNCT) (3;4). CH is the most common form of TAC. The 1-year prevalence is 
about 1 in 1000, with the vast majority of patients having episodic CH (ECH): periods 
of weeks to months with frequent attacks which are alternated with symptom-free 
periods of several months to years. About 10% have chronic CH (CCH): attack free 
periods of less than one month in every 12 months, unless treatment is given. The 
chronic form can be primary unremitting from onset, or can be secondary, transform 
from the episodic form. CCH may spontaneously become episodic. 
2.2 Treatment 
Effective acute treatments for CH attacks are injectable or intranasal triptans and 
oxygen inhalation. Steroids (only for a short period), verapamil, lithium carbonate and 
methysergide are the most effective preventive therapies. At least 10% of patients 
with CCH is or may become refractory to or cannot tolerate medical therapy. For 
patients with medically intractable CCH (MICCH) there is no common treatment. 
Different experimental treatments, such as deep brain stimulation (DBS), 
radiofrequency lesions, glycerol injections, gamma knife, and surgery or root section 
of the trigeminal nerve are either substantially ineffective, or have significant short-
comings with serious complications such as death or neurological deficits such as 
anaesthesia dolorosa or lack of efficacy. 
2.3 Social and economic impact 
CH has considerable impact on socio-economic and personal functions due to direct 
costs of healthcare services and indirect costs of lost work days and decreased work 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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efficacy (5). Higher pain scores and a higher percentage of patients with poor health 
due to pain and social functioning are found among CH patients compared with 
patients suffering from migraine (6). The impact on social functions, quality of life 
and use of healthcare of patients with MICCH is most likely even larger, although 
precise figures are not available. In the study of Burns et al. (7) patients, suffering 
from MICCH, had on average over four attacks per day. Attacks of CH have been 
described by patients as being worse than child birth. Recently treatment of headache 
was listed as one of the top priorities of US National the Institute of Medicine’s 
agenda for comparative-effectiveness research (8). 
2.4 Hypothalamic deep brain stimulation 
Functional imaging studies in CH identified activations in the region of the posterior 
hypothalamus, which led to the use of neurostimulation therapy in MICCH. 
Hypothalamic DBS was shown to be effective in some patients with MICCH but 
unfortunately this treatment is associated with a high risk of (even lethal) 
consequences (9-12). 
2.5 Stimulation of the suboccipital nerve in CH 
Structures in the occipital region of the head are mainly innervated by the greater 
occipital nerve that is a branch of the C2 spinal root. Convergence of cervical, somatic 
trigeminal and dural trigeminovascular afferents on second order nociceptors in the 
brain stem is well documented (13-16).  
 
 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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Figure.—Illustrated are the elements of the anatomy and physiology of 
the trigeminocervical complex with both dural (trigeminal) and cervical 
afferents projecting to thalamus and cortex.  
Periaqueductal grey matter (PAG), rostroventral medulla (RVM), central nervous system (CNS). 
 
Source: Occipital Nerve Stimulation for Headache: 
Mechanisms and Efficacy 
Goadsby P.J. et al., Headache, 2008, (16) 
 
Stimulation of the greater occipital nerve increased metabolic activity in cervical 
regions of the spinal cord and in the trigeminal nucleus caudalis in the cat (14). In 
humans an occipital nerve blockade decreased the ipsi- and contralateral R2 response, 
confirming the anatomic and functional convergence of afferent cervical and 
trigeminal pathways (17). These studies suggest that modulation of these pathways 
may influence headache. 
 
Suboccipital injection of corticosteroid with local anaesthetics was shown to be 
effective in a placebo-controlled trial (18). In this study 4 patients suffering from 
CCH were included. In all patients the attacks recurred eventually. The authors 
suggest that suboccipital steroid injections ought to be tried as a single shot treatment 
before invasive treatments are considered such as DBS, but in later studies this turned 
out to be of no predictive value of the response to neuromodulation therapies 
(9;19;20).  
 
Along the same line, stimulation of the greater occipital nerve (ONS) has been tried 
with some success in intractable headaches including CCH (7;19-22). Burns et al. 
described 14 patients suffering from MICCH and were treated with ONS in an open 
retrospective study. Ten patients improved; three improved by 90% or more, 3 by 
40%-90% and 4 by 20-30%. (7;23).  In a prospective open ONS study on MICCH  
patients Magis et al. showed a reduction in attack frequency of 79.9% (20). No 
serious complications were described in both studies.  
 
3. Study Rationale 
There is no established treatment for patients with MICCH. ONS has been used in 
open label trials with promising results (7;19-22).  A prospective, randomised, 
controlled clinical trial is necessary to assess the efficacy, tolerability and safety of 
ONS in the treatment of MICCH.  

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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4. Study design 
This is a prospective, randomised, double blind, parallel group multi-centre 
international clinical study to compare the reduction in attack frequency from baseline 
of occipital nerve stimulation (ONS) in patients with MICCH between two different 
stimulation conditions: high (100%) and low (30%) stimulation. (see paragraph 10.1) 
 
Active ONS is associated with paraesthesias complicating blinded comparison versus 
no stimulation. From our own experience with patients treated with ONS, we know 
that patients might find it difficult to differentiate paraesthesias associated with 100% 
and 30% stimulation. Recognition of the stimulation intensity would be further 
complicated by stepwise increasing the stimulation intensity.  
 
 
 
 
Patients will be included for a 3 month baseline period, of which the first month 
serves for practice only. If the patient still meets the inclusion criteria after this 
baseline period, he/she will be randomised and scheduled for surgery. Following 
surgical implantation there will first be a run-in phase of 10 days of 10% stimulation 
intensity until wound check, followed by a stepwise increase up to either 30% or 
100%. Patients in the 100% stimulation arm will receive this intensity for 4 months. 
randomisation 
100% stimulation
30% stimulation
6 months of  
stepwise increase 
6 months of 
stepwise increase 
  Baseline 
3 months 
6 months 
6 months 
100% or best 
stimulation 
10%
10%
Month:      1      2       3      4        5          6 
              10%  10%  20%  20%    30%   30% 
                40% 70% 100% 100% 100% 100%  
Month: 1       2        3        4        5         6 
10 days 
implant 
implant 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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Patients will be assessed every month by the blinded study neurologist. If the patient 
finds the stimulation painful in between follow-up moments, an extra follow-up 
moment will be arranged soon and the threshold for discomfort will be defined again. 
The primary outcome measure is the number of attacks over the last 4 weeks of the 
double blind 6 month treatment period. Hereafter, in an open extension phase of 6 
months, all patients will receive 100% stimulation or the stimulation considered 
optimal by the patient. The patients will fill in an (electronic) diary during the whole 
study period. 
 
Rationale design 
We estimated the effect of ONS in three Dutch patients. We found that sensation 
threshold and discomfort threshold can be repeatedly defined and that patients could 
not distinguish small differences in stimulation. 
 
A similar design was successfully used in a multicenter, prospectively randomised, 
parallel, double-blind study that showed that high vagus nerve stimulation gave 
significantly more reduction in seizure frequency than low vagus nerve stimulation 
(24). This finding supports a proposed dose response in neurostimulation and 
subsequently supports our design. Supposed treatment allocation by the patient, on the 
other hand, was not mentioned in this study.  
 
Matharu et al. (25) showed a correlation between mean pain scores, stimulator 
induced paresthesia and changes in regional cerebral blood flow in ONS treated 
chronic migraine patients. These findings suggest a dose related effect of the 
stimulation and thereby supports our design. 
 
Blinding 
Patients, neurologists and the study investigator will be blinded for the randomisation. 
The IPG programming (not blinded) will be performed by the implanter 
(neurosurgeon or anaesthesiologist) or research nurse. They will take precautions to 
ensure that patients are unaware of their randomisation status by not informing them 
about the stimulation conditions. 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
13 
Procedure 
 
 
 
 
Initial screening study 
neurologist: 
Inclusion & Exclusion criteria 
Consultation Study coordinator: 
Not eligible 
reject 
Meets criteria:  
Schedule meeting implanter (and study coordinator) 
Explanation: study, informed consent, headache diary 
Informed consent 
Start headache diary baseline 
Visit anaesthesiologist  
3 months 
Interview telephone (economic evaluation)  
Schedule surgery 
Randomisation 
ONS all patients 
Adjust stimulation parameters: define 
sensation threshold and discomfort 
2-3 days in 
hospital 
Not eligible 
reject 
No longer meets 
criteria 
Withdraw 
Evaluation headache diary study 
coordinator 
Screening 
Study flow chart 
After 10 days wound 
check and stimulation 
adjustment 
Stim 10% 
2 months 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
14 
Follow-up 
Follow-up second period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
visit month 4: 
stimulation 
check 
6 months 
Interview telephone (economic evaluation) 
Open trial 100% stimulation or best 
stimulation 
  
40% 
stim 
10% 
stim 
10% 
stim 
70% 
stim 
20% 
stim 
100% 
stim 
100% 
stim 
20% 
stim 
100% 
stim 
30% 
stim 
30% 
stim 
100% 
stim 
visit month 1: 
stimulation 
check 
visit month 2: 
stimulation 
check 
visit month 6: 
stimulation 
check 
visit month 9: 
stimulation 
check 
visit month 
12: 
stimulation 
check 
6 months 
monthly visit study 
neurologist 
1 month 
1 month 
1 month 
1 month 
monthly visit study 
neurologist 
monthly visit study 
neurologist 
(option: by telephone) 
monthly visit study 
neurologist 
monthly visit study 
neurologist 
3 monthly visit 
study neurologist 
monthly visit study 
neurologist 
(option: by telephone) 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
15 
 
 
T=6 
12 months 
after 
surgery 
± 4 
weeks 
 
 
 
X 
X 
 
X 
X 
T=5 
9 months 
after 
surgery 
± 4 
weeks 
 
 
 
X 
X 
 
 
X 
T=4 
6 months 
after 
surgery 
± 2 
weeks 
 
 
 
X 
X 
X 
X 
X 
T=3 
4 months 
after 
surgery 
± 2 
weeks 
 
 
 
X 
X 
 
 
X 
T=2 
2 months 
after 
surgery 
± 1 week 
 
 
 
X 
X 
 
 
X 
T=1 
1 month 
after 
surgery 
± 1 week 
 
 
 
X 
X 
 
 
X 
T=0 
10 days 
after 
surgery 
± 2 days 
 
 
X 
 
X 
 
 
X 
T=-1  
Interventio
n 
 
 
X 
X 
 
X 
 
 
X 
T=-2  
Pre-op 3 
months 
after 
inclusion 
 
 
 
 
X 
 
X 
 
X 
T=-3 
Inclusion 
start 
electronic 
diary 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Visit 
Window 
Patient 
characteristi
cs 
Intervention 
Wound 
inspection 
Headache 
diary 
Stimulation 
and system 
check 
Economic 
evaluation 
questionnaire 
Patient 
satisfaction 
Adverse 
events 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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5. Patient recruitment  
Patients will be recruited from tertiary headache clinics in The Netherlands, Denmark, 
UK and probably Belgium and Germany. 
 
6. Study Purpose 
Objectives 
The primary objective of this study is to investigate whether ONS reduces the attack 
frequency in MICCH compared to baseline.  
 
7. Endpoints 
7.1 Primary 
The primary endpoint is the mean attack frequency (MAF) over the last 4 weeks in 
the 100% and the 30% treatment groups at 6 months.  
An attack is defined as any attack recognised by the patient as being a CH attack. So 
also the attacks treated with oxygen or triptans.  
(For consistency of calculation, any reference in this document to a month shall mean 
a period of 4 weeks.) 
 
7.2 Secondary 
MAF: We will repeat the primary analysis, with the MAF as outcome instead of the 
logarithm of the MAF. 
MAF during follow-up: The MAF for each 4 week period of the whole follow-up 
period. 
Mean attack intensity: The mean attack intensity (on a scale from 0-10) will be 
calculated over the last 4 weeks for each group at baseline, 6 and 12 months follow up 
and will be compared between and within the 2 groups. 
Responder rate: Rate of responders (>50% reduction in attack frequency in the last 4 
weeks compared to baseline) will be calculated and compared between groups at 6 
and 12 months. 
Economic evaluation: see paragraph 11. 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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Anticipated group randomisation: The patient and assessors will be asked at 6 months 
follow-up (before deblinding), in which treatment group (high or low stimulation) 
they think the patient was allocated. 
Awareness of paraesthesias: localisation and strength will also be evaluated weekly 
and coded through the patients’ recordings in the electronic diary and compared with 
effectiveness of stimulation, e.g. frequency of attacks. 
 
Picture used to code location of stimulation. 
From: Stimulation Ranges, Usage Ranges, and 
Paresthesia Mapping During Occipital Nerve 
Stimulation 
Trentman T.L. et al., Neuromodulation, 2008 (26) 
 
 
The use of acute attack medication: The number of doses of sumatriptan injections or 
intranasal spray or O2 inhalation periods will be investigated and calculated of the last 
4 weeks of each treatment period and the baseline period, and compared between and 
within groups.   
Patient satisfaction: We will ask the patient at 6 and 12 months follow-up whether 
he/she would recommend the treatment to another patient using a 5 point (Likert) 
scale: Strongly disagree, disagree, neither agree nor disagree, agree, strongly agree. 
Responder identification: It is also investigated whether predictive factors can be 
identified with respect to the outcome in a hypothesis generating manner. We will 
look at the body mass index (BMI) and assess the predictive value of response after 5-
7 days. 
Adverse events: All and treatment-related adverse events will be documented by the 
investigators.  

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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8. Patient Selection Criteria 
Diagnosis of patients with CH shall be in accordance with The International 
Classification of Headache Disorders, 2nd Edition: (1)  
 
A. At least 5 attacks fulfilling criteria B–D 
B. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 
15-180 minutes if untreated 
C. Headache is accompanied by at least 1 of the following: 
1. ipsilateral conjunctival injection and/or lacrimation 
2. ipsilateral nasal congestion and/or rhinorrhoea 
3. ipsilateral eyelid oedema 
4. ipsilateral forehead and facial sweating 
5. ipsilateral miosis and/or ptosis 
6. a sense of restlessness or agitation 
D. Attacks have a frequency from 1 every other day to 8 per day 
E. Not attributed to another disorder 
 
Chronic cluster headache 
A. Attacks fulfilling criteria A–E for Cluster headache 
B. Attacks recur over >1 year without remission periods or with remission periods 
lasting <1 month 
 
8.1 Inclusion Criteria 
• ICHD-II criteria for CCH (see above) 
• Minimum mean attack frequency of 4 attacks per week  
• Minimum age of 18 years old 
• Signed study specific informed consent form agreeing to implantation of 
the device, data collection and follow-up requirements 
• Agreeing to refrain from starting new prophylactic CH medication, 
including steroids, or any other therapy aimed at CH (such as acupuncture, 
biofeedback, chiropractic, or massage) and agrees to maintain existing 
prophylactic CH medication from 4 weeks before entering the baseline 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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period throughout the duration of the double blind phase of the study. It is 
allowed to change the dose of prophylactic medication during the study 
based on the opinion of the treating medical specialist. 
• Availability during follow-up period 
• An MRI not older than 4 years prior to enrolment must be available to 
exclude structural lesions potentially causing CCH. An exception can be 
realized by the study coordinator in case of stable CH for over 4 years and 
no change in symptoms after the last MRI scan was performed.  
• MRA of head and neck are to be performed according to study physician’s 
individual judgement.  
• Medically intractable (see below) 
 
Definition medically intractable :(2) 
Failed adequate trials of regulatory approved and conventional treatments according 
to local national guidelines  
 
Current prophylactic treatment of CH consists of corticosteroids (short term only), 
methysergide (short term only), verapamil and lithium. Other drugs, such as 
valproate, pizotifen, topiramate and gabapentin are also used without clinical evidence 
(27). Prolonged treatment with methysergide has been associated with fibrotic 
reactions and therefore is no longer available in the USA and some other European 
countries. Corticosteroids are often efficacious, but treatment should be limited to 6-8 
weeks. For this reason patients do not have to be intractable for corticosteroids to be 
included in the study. Verapamil is the preventive drug of choice in CCH, followed by 
lithium (28).  
 
Adequate trial: 
Appropriate dose and duration of treatment according to local guidelines 
Appropriate length of time  
Consideration of medication overuse 
 
Failed:  
No therapeutic or unsatisfactory effect, intolerable side effects, contraindications to 
use 
 

Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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Must have tried agents of at least three classes of the following, of which 1 and 2 are 
obligatory, and 1 should come from 3-5: (recommendation of Goadsby et al. applied 
to Dutch national guidelines) (2) 
 
1 Verapamil 
2 Lithium 
3 Methysergide 
4 Topiramate 
5 Gabapentin        
       
8.2 Exclusion Criteria 
• Other significant neurological or disabling diseases (including other forms of 
TAC) which in the opinion of the clinician may interfere with the study 
• Pregnancy or the wish to become pregnant during the study period 
• Cardiac pacemaker and other neuromodulatory devices 
• Psychiatric or cognitive disorders and/or behavioural problems which in the 
opinion of the clinician may interfere with the study  
• Taking CH prophylactic medication for conditions other than CH which in the 
opinion of the clinician may interfere with the study  
• Serious drug habituation and/or overuse of acute headache medication (use on 
10 or more days per month) for other headaches than CH 
• Inability to complete the (electronic) diary in a sensible and accurate manner 
• Structural intracranial or cervical vascular lesions that may potentially cause 
CH 
• Previous destructive surgery involving the C2 or C3 roots (vertebrae) or deep 
brain stimulation  
• Enrolment in other clinical studies that may confound the results of this study 
• Requiring anticoagulation therapy or antithrombotic or thrombocyte 
aggregation-inhibitor for a concomitant condition that cannot be stopped peri-
operatively. The local peri-operative protocol of each individual participating 
centre will be followed 

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9. Protocol Description 
 
9.1 Detailed research plan 
When a patient meets all eligibility criteria, the neurologist from the participating 
centre will discuss the case with the study coordinator and/or refer to a study 
neurologist. There will also be a consultation of the study implanter. When it is 
decided that the patient can be included for the study, there will be an informed 
consent first. It will approximately take two months to schedule the surgery. The 
patient will undergo the pre-operative screening and will fill in a daily (electronic) 
diary for four weeks to practice first, followed by eight weeks before surgery. 
Randomisation will take place if the patient still fulfils eligibility criteria after 
completing the pre-operative headache diary for 12 weeks. The surgery will be 
planned in advance because of potential waiting lists. 
 
Pre-operative evaluation 
 
 
• Written informed consent  
• Common internal and neurological examination 
• Pre-operative consultation of an anaesthesiologist 
• MRI must be available (not older than 4 years) or performed and must be 
repeated after any changes in symptoms to exclude an underlying cause of the 
CCH. MRA of head and neck may be performed according to study 
physician’s individual judgement.  
Questionnaire (in ProMISe): 
• medical history, medication use now and in the past, course of the disease 
(PCCH or SCCH), social habits: smoking, alcohol, coffee, previous response 
to medication: intolerability or no or little response) 
Electronic headache diary for 12 weeks (of which 4 are to practice) (in ProMISe): 
• Each attack of CH 
• Pain intensity (0-10) during the last 6 weeks of baseline and each treatment 
period (of which the first 2 are for practice) 
• Number of attacks per day of CH and other forms of headache  

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• Use of prophylactic or acute medication  
• Monthly SF-36 questionnaire 
 
Interview by telephone: 
• A questionnaire about health consumption and absenteeism from work 
 
The operating neurosurgeons or anaesthesiologists will use a uniform technique, 
described in section 10.2 in this protocol.  
 
9.2 Schedule 
Visit 1: study neurologist: inclusion/exclusion criteria 
 
Visit 2: visit neurosurgeon (or implanter)/investigator: information about the surgery 
and study: reflection period of 7-14 days (or as long the patients needs) 
 
Visit 3: informed consent study neurologist. Start electronic diary 
 
Visit 4: anaesthesiologist  
 
Evaluation headache diary by study coordinator: does the patient still meet inclusion 
criteria: at least 4 attacks per week? 
 
Interview by telephone (medical student): economic evaluation questionnaire 
 
Randomisation 
 
Visit 5: surgery and defining stimulation parameters: 2-3 days in hospital 
 
Visit 6: +10 days control of wound and removal of stitches t=0 and calibration of 
stimulation 
 
Visit 7: + 1 month: checking and changing of stimulation follow-up  
 
Visit 8: + 2 months checking and changing of stimulation follow-up  
 
Visit 9: + 4 months: checking of stimulation follow-up  
 
Interview by telephone (student) after 6 months: economic evaluation questionnaire 
 
Visit 10: + 6 months: checking of stimulation follow-up  
 
Plus monthly visits study neurologist (an exception will be made for the visits at 3 and 
5 months follow-up, because in case the participating patient prefers a telephone call 
instead, this will be allowed) 

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Open trial: 
 
Visit 11: + 9 months: checking of stimulation follow-up  
 
Visit 12: + 12 months: checking of stimulation follow-up  
 
Plus three-monthly visit study neurologist 
 
 
 
9.3 Interview by telephone 
The patient will be interviewed by telephone twice by a medical student to answer a 
questionnaire about health consumption and absenteeism. 
 
9.4 Data  
 The study coordinator is involved in coordination, collecting and analysing data.  
 
9.5 Stimulation parameters 
Setting stimulation parameters will be done by one of the case-managers (specialized 
nurses), the neurosurgeon or the anaesthesiologist who implanted the device (not 
blinded). 
 
9.6 Surgery and hospital visits 
The period of surgery and defining and adjusting the stimulation parameters will take 
approximately 2-3 days. After 10 days, the patient returns to the hospital for 
examination of the wound and removing stitches and test the system (impedances), 
and calibration of stimulation. After month 1, 2, 4 and 6 the patient will return to the 
clinic for evaluation and stimulation adjustments. The study neurologist will be seeing 
the patient on a monthly basis during the blinded part of the study(with the exceptions 
of visits 3 and 5 months follow-up which can be replaced by telephone calls in case 
the patient prefers this); this will be on a 3-monthly basis during the second part. 
During these evaluations the following scores will be taken (in the electronic diary or 
during an interview): for details see appendix 24.1  

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Electronic diary in Promise:   
• Medication use 
• Frequency of attacks of CH and other headache attacks 
• Intensity of attacks: Numeric pain rating scale (only during the 6th and 12th 
month and 2 weeks before for practice) 
• Absenteeism from work  
• The awareness of paraesthesias: localisation (coding system) and strength (0= 
no paraesthesias 10= strongest paraesthesias 
• Monthly SF-36 
Interview: 
• Adverse events; painful stimulation, neck stiffness, uncomfortable feeling of 
the device, infection, lost sensation of stimulation, when suspected lead 
migration: X-ray cervical spine 
• Patient satisfaction 
Before evaluations patients fill in their daily electronic diary, which will be send to 
our database after every 7 days (the patients will get a reminder per email or 
telephone). In the case of holiday, or not possessing a computer with internet access 
or another reason that discourages the patients from filling in the electronic diary, the 
patient receives a hard copy form of the diary, which can be copied to the electronic 
diary later. 
 
At 6 and 12 months post randomisation, all patients return to the study neurologist/ 
study coordinator for the final recording of the headache diary and interview. The 
patient will be asked at  6 and 12 months follow-up to which group they think they 
have been randomised in the first 6 months treatment period and if he/she would 
recommend the treatment to other patients. 
 
After ending the study, the study patients will be able to continue the study treatment 
on compassionate grounds. This will mean that they will continue to receive treatment 
at the study centre as is necessary for the ONS.  
 
 
 

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10. Methods 
 
10.1 Defining stimulation amplitudes 
The amplitude of stimulation will be established for each individual patient by 
determining the patient’s individual therapeutic range as described in Trentman et al. 
(26). They found a mean amplitude for perception of 1.07 V and discomfort of 3.63 
V. Stimulation frequency and pulse width will be uniformly held constant at 60 Hz 
and pulse width at 450 s. The perception and discomfort amplitude will be defined 
by increasing the stimulation amplitude in steps of 0.1 V. The head will be in neutral 
position. The amplitude at which the patient starts feeling paraesthesias is called the 
perception threshold. The threshold at which the patient does not want the voltage to 
be increased any further because of painful sensations is designated the discomfort 
threshold. 100% stimulation is defined as stimulation at 90% of the range between 
perception and discomfort thresholds. Consequently, 30% stimulation means a 
stimulation level at 30% of the range between perception threshold and 100% 
stimulation level. The same goes for the 10%, 20%, 40% and 70% stimulation. 
Defining these thresholds will be done using a standard method by trained nurses or 
doctors and will be repeated 3 times, and only accepted if the values differ no more 
than 20%. The procedure will be repeated until the values differ no more than 20%. 
 
Definitions: 
DT: Discomfort threshold 
PT: Perception Threshold  
SL100% stimulation: 100% stimulation level 
 
Formula: 
SL100%  = PT + 0.9 x (DT-PT) 
 
SLX% = PT + (SL100% - PT) x X/100 
 
Example: PT: 1.0 V and DT: 6.0 V.  
 
SL100%  = 1.0 + 0.9 x (6.0-1.0) = 5.5V.  

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SL20% = 1.0 + (5.5-1.0) x 20/100 = 1.9 V 
 
SL70%  = 1.0 + (5.5 – 1.0) x 70/100 = 3.3 V 
 
10.2 Surgery 
Since there will be no trial stimulation, the proposed abdominal location of the 
Implantable Pulse Generator (IPG) should be discussed with the patient on 
beforehand. In case of contra indications according to the patient or implanter for 
placement of the IPG abdominal, another location will be chosen for instance on the 
buttock. The procedure is performed under general anaesthesia and antibiotic 
prophylaxis: Cephalozin 1 or 2 g (according to local guidelines) (when the patient is 
allergic to certain antibiotics, please consult the hospital microbiologist for advice) 
given half an hour prior to actual surgery. The procedure will be done in two tempi. 
First the patient is positioned in a prone position with his/her head facing downwards 
in an adjustable U shaped headrest. After removing hair from the upper neck/lower 
occipital area using a clipper and disinfecting twice the area from low occipital to the 
left flank, an incision drape is used when sterile draping is applied to the surgical site. 
Using fluoroscopy the skin is marked at the level of vertebral arc C1. Here, a small 
area is infiltrated with a mixture of Lidocain(10mg/ml) /Epinephrine(5mcg/ml), 
before a small (2 cm) cranio-caudal incision is made. A 2-3 cm diameter 
subcutaneous pocket is prepared. The Touhy needle is slightly bent and then under 
fluoroscopic guidance inserted in lateral direction just beneath the skin and outside the 
fascia. The Quad Plus® (56 cm length; or shorter according to the length of the 
patient and preference of the implanter) is inserted after the stylet is removed. It is 
advanced until all electrodes are covered, then the Touhy needle is removed whilst 
keeping the lead in place. The lead is secured with a Titan anchor® that is fixed to the 
midline-fascia in the pocket with nonresorbable sutures (Mersilene® 1-0). By slightly 
pulling the lead the fixation is checked. 
 
On the contralateral side, exactly the same procedure is performed. With the lead 
passer the lead is then subcutaneously led to the left flank, an in-between incision may 

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be required. The lead is looped at least two sites along the way, to avoid inadvertent 
damage by possible traction. Finally all wounds are sutured. 
 
In a second period the patient is positioned laterally, right side facing down. The 
surgical area (flank towards left abdomen or buttock where the agreed upon spot is 
marked for the IPG) is disinfected twice and sterile (incision) drapes applied. A 7-8 
cm paraumbilical incision is made at the marked site, a pocket (5x5 cm) is made using 
blunt dissection (no monopolar cautery allowed) in the subcutaneous fat layer over the 
abdominal fascia. The incision in the flank is re-opened and a small pocket (3x3 cm) 
is made there as well. From here the passer is inserted to the abdominal pocket. The 
lead extensions are pulled through and connected to the leads. The connection is 
covered by a silicon sheet fixed with nonresorbable sutures. The extension cables are 
connected to the IPG (Versitrel™) which is implanted into the pocket and secured 
with 1 or 2 nonresorbable sutures. The N’vision™ programmer is used to analyse 
impedances of this neuromodulation system. When there are no system failures, 
remaining wounds are sutured.  
SUMMARY: Low occipital bilateral Quad Plus, midline to laterally directed, secured 
by titan anchors, connected to Versitrel. No trial stimulation. Suggested stimulation 
parameters: Pulse width: 450, Amplitude: protocol, Rate: 60. 
 
10.3 Devices used 
IMPLANTABLES (Medtronic order nr)if a Versitrel IOG is used: IPG: Versitrel™ 
(7427V), Extension cable: Low profile Quad extension cable 10-60 cm, length 
depends on patient characteristics (7489 10-60), Lead: Pisces Quad® Plus 56 cm 
(388856) (or a different length), Fixation: Titan Anchor® (3550-39), Versitrel™ 
Patient Programmer (7435) 
It is also allowed to use the Prime Advanced IPG (37702) with compatible extension 
cables in stead of the Versitrel IPG, as this IPG the ‘newer version’ of the Versitrel 
(7427V) and some implantation sites are more common with this. The most important 
difference is the more advanced software, which will only matter to the nurse or 
doctor adjusting the stimulator, because it is easier in use. We don’t think the 
participating patients will be caused disadvantage by using either IPG. 

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IMPLANTABLES (Medtronic order nr) if a Prime Advanced IPG is used: Prime Advanced™ 
(37702), Bifurcated extension cable 20-40-60 cm, length depends on patient characteristics 
(37082-20/ -40/ -60), Anchor injex bumpy or injex bi-wing (97791 or 97792),  Plug (3550-
29), 2 Quad-plus electrode 28-33-45-56 cm, length depends on patient characteristics (3888-
28/ -33/ -45/ -56), Trialling cable (3555-31), Mystim (97740). 
 
11. Economic evaluation 
 
The objective of the economic evaluation part of this study is to examine whether the 
delivery of high (100%) stimulation compared to low (30%) stimulation is preferable 
in terms of costs, effects and utilities from a societal perspective. 
 
11.1 Design and participants 
Economic evaluations compare additional costs and additional outcomes of high 
stimulation compared to low stimulation. This economic evaluation will involve a 
combination of a cost-effectiveness analysis (CEA) and a cost-utility analysis (CUA). 
In a CEA effects are presented in clinical outcomes (in our study frequency of CH 
attacks during the last 4 weeks of the 100% stimulation period and the 30% 
stimulation period).  The primary outcome measure for the cost-utility analysis will be 
Quality Adjusted Life Years (QALYs), based on the SF-36 utility scores (29-31). In 
the CUA, the Incremental cost-effectiveness ratio (ICER) will be expressed as the 
incremental costs per QALY. This economic evaluation will be performed from a 
societal perspective, which implies that all relevant costs and outcomes will be taken 
into account. With regard to this research question we hypothesize that the high 
stimulation is associated with an increased effect, and an increase in quality of life. 
The time horizon will be the same period as the follow-up period of the double blind 
part of the main study, 6 months. Costs (the use of resources) will be measured 
continuously using a (retrospective) questionnaire (6 months); outcomes for the 
economic evaluation study will be measured at pre-test before random assignment 
into groups (baseline), and at 6 months.  
 
The second part of this economic evaluation will be a cost-of-illness (COI) study. 
The objective of this COI analysis is to calculate the societal costs of MICCH in the 
Netherlands. This prevalence based, retrospectively and bottom-up cost of illness 

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study will be performed at baseline using a (retrospective) questionnaire (6 months) 
and an electronic diary for the use of attack medication.   
 
 
11.2 Measurement 
Cost measures 
Total costs will be estimated using a bottom-up (or micro-costing) approach, where 
information on each element of service used is multiplied by an appropriate unit cost 
and summed to provide an overall total cost (32). We will assess intervention costs, 
healthcare costs, patient and family costs, and costs outside the health care sector. For 
this study we developed a cost questionnaire especially designed for this group, based 
on existing questionnaires, which will identify all relevant costs aspects (33;34).  
 
To measure the actual use of resources data will be obtained using combined sources 
(registrations by professionals and cost questionnaire). Resources used relating to the 
interventions will be based on the registered time all professionals spent on the 
treatment. Intervention costs will include all the costs that will contribute to the 
procedure of ONS. All use of resources by the patient and their family in and outside 
the health care sector, will be measured by means of an interview by telephone, in 
which they are being asked about volumes of resource utilization 6 months 
retrospectively at baseline and at 6 months follow up. Cluster headache medication 
use will be registered in the electronic diary. These 2 sources of information will be 
combined. 
 
The valuation of healthcare costs, patient and family costs will be based on the 
updated Dutch manual for cost analysis in healthcare research (35;36). This manual 
recommends using standardized cost prices. In brief, the manual recommends that 
prices of informal care will be based on shadow prices for unpaid work (meaning a 
standard cost price based on general hourly wages). Costs of medication will be 
calculated using prices taken from the Dutch Pharmacotherapeutic Compass (37). 
Productivity costs will be calculated by means of the friction cost method, based on a 
mean added value of the Dutch working population. The friction costs method takes 
into account production losses confined to the period needed (usually 90 days) to 
replace a sick employee. In case of uncertainty we will use a conservative estimation 

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(i.e. the lowest cost price). Cost prices will be expressed in 2009 euro’s. If necessary, 
existing cost-prices will be updated to 2011 using the consumer price index (CPI) 
(35;36). 
 
Outcome measures 
The primary outcome measure for the cost-effectiveness analysis will be increase in 
health status as measured by the CH attacks 4-weekly at 6 months of follow-up of the 
last month of both treatment arms. Within the cost-utility analysis, utilities will be 
derived using an indirect preference-based technique. In this technique, the patient’s 
health status will be monthly measured by means of the standard Dutch version of SF-
36 and weights, that incorporate preferences from a general population sample, will 
be used to calculate utilities from the SF-36; the Short Form 6D (SF-6D) (29;31). The 
SF-36 will be completed monthly in the electronic diary and the cost questionnaire 
will be completed at baseline and at 6 months follow-up by an interview by telephone. 
The SF-36 is chosen because it is a widely used quality of life instrument (nationally 
and internationally), also in the field of headache (38). Utility values can be calculated 
for these health states, using preferences elicited from a general population, the so-
called Brazier algorithm (29). The utility values derived from the Brazier algorithm 
will be used to compute QALYs. The Brazier algorithm has been established using a 
general population from the UK (29). The utilities at the time points will be used to 
compute a QALY score by means of the area under the curve method. 
 
 
11.3 Analysis  
No power calculations will be performed for the economic evaluation study as it is 
embedded in an RCT. Our primary (base-case analyses) will be performed according 
to the intention-to-treat principle, including data from all participants regardless of 
whether they received the intervention or not. For the analyses we will use SPSS 
statistical software and Excel database (for the Bootstraps).  
 
To investigate whether data are normally distributed a Kolmogorov-Smirnov test will 
be performed. Despite the usual skewness in the distribution of costs, the arithmetic 
means will be generally considered the most appropriate measures to describe cost 

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data (39;40). Therefore arithmetic means (and standard deviations) will be presented. 
In case of skewness of the cost data, non-parametric bootstrapping will be used to test 
for statistical differences in costs between the 100% stimulation and the 30% 
stimulation group. Non-parametric bootstrapping is a method based on random 
sampling with replacement based on individual data of the participants (41). The 
bootstrap replications will be used to calculate 95% confidence intervals around the 
costs (95% CI), based on the 2.5th and 97.5th percentiles. If cost data are distributed 
normally, t-tests will be used.  
 
The ICER will be determined on the basis of incremental costs and effects of high 
stimulation compared to low stimulation. The cost-effectiveness ratio will be stated in 
terms of costs per outcome rate, the cost-utility ratio will focus on the net cost per 
QALY gained. The ICER will be calculated as follows. ICER = (Ci – Cc) / (Ei – Ec), 
where Ci is the annual total cost of the high stimulation group, Cc is the annual total 
cost of the low stimulation group, Ei is the effect at one year follow-up for the high 
stimulation group and Ec is the effect at one year follow-up for the low stimulation 
group. The robustness of the ICER will be checked by non-parametric bootstrapping 
(1000 times). Bootstrap simulations will also be conducted in order to quantify the 
uncertainty around the ICER, yielding information about the joint distribution of cost 
and effect differences. The bootstrapped cost-effectiveness ratios will be subsequently 
plotted in a cost-effectiveness plane, in which the vertical line reflects the difference 
in costs and the horizontal line reflects the difference in effectiveness. The choice of 
treatment depends on the maximum amount of money that society is prepared to pay 
for a gain in effectiveness, which is called the ceiling ratio. Therefore, the 
bootstrapped ICERs will also be depicted in a cost-effectiveness acceptability curve 
showing the probability that high stimulation is cost-effective using a range of ceiling 
ratios.  
Additionally, to demonstrate the robustness of our base-case findings a multi-way 
sensitivity analyses will be performed. In the sensitivity analysis uncertain factors of 
assumptions in the base case analysis will recalculated in order to assess whether the 
assumptions have influenced the incremental cost-effectiveness ratio (ICER), for 
example by varying cost-prices and volumes between minimum and maximum (41). 
 

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11.4 Cost-of-illness (COI) 
The objective of this COI analysis is to calculate the societal costs of MICCH in the 
Netherlands. This prevalence based, retrospectively and bottom-up cost of illness 
study will be performed at baseline. Data for this COI will come from the baseline 
measurements of the a cost questionnaire especially designed for this group, based on 
existing questionnaires, which will identify all relevant costs aspects (33;34). The 
valuation of the COI will be based on the same methods as used in the economic 
evaluation (37). 
 
12. Protocol deviations 
 
Investigators are required to adhere to the Investigational Plan, signed Investigator’s 
Agreement, applicable national or local, laws and regulations, and any conditions 
required by the appropriate Ethics Committees (EC) or applicable regulatory 
authorities. 
 
Deviations from the protocol will not be permitted, except where necessary to protect 
the life or physical well-being of a patient in an emergency situation. If circumstances 
permit, the investigator should inform study management before initiating deviations. 
Prior notification is generally not expected in situations where unforeseen 
circumstances are beyond the investigator’s control (e.g. patient did not attend 
scheduled follow-up visit). The investigator is required to adhere to the EC 
procedures for reporting deviations. Deviations include, but are not limited to the 
following: 
• Failure to obtain informed consent prior to patient enrolment 
• Incorrect version of the informed consent form used 
• Enrolled patient did not meet the inclusion/exclusion criteria 
• Adverse Events not reported by investigators in the required timeframe as 
specified in the protocol  
 
Centre compliance with regard to deviations will be reviewed by the study 
coordinator on a timely basis. In addition, all deviations from the CIP will be 
documented in the final report. 
 

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13. Safety monitoring 
The study investigators are responsible for the detection and documentation of 
adverse events (AEs) and device events.  
 
13.1 Adverse Event Definitions 
Definition/classification  
For the purposes of the clinical report, each adverse event will be classified according 
to EN ISO 14155-1. 
Where the definition indicates “device”, it refers to any device used in the study. This 
might be the device under investigation, or any market released component of the 
system. 
 
13.2 Adverse Event (AE):  
Any untoward medical occurrence in a subject. 
NOTE 1: This definition does not imply that there is a relationship between the 
adverse event and the device under investigation.   
 
13.3 Adverse Device Effect (ADE):  
Any untoward and unintended response to a medical device. 
NOTE 1: This definition includes any event resulting from insufficiencies or 
inadequacies in the instructions for use or the deployment of the device. 
NOTE 2: This definition includes any event that is a result of a user error. 
NOTE 3: This definition includes patients and users.  
 
13.4 Serious Adverse Event (SAE):   
An adverse event that  
a) led to death 
b) led to a serious deterioration in the health of a subject that  
 
1) resulted in a life-threatening illness or injury,  

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2) resulted in a permanent impairment of a body structure or a body function,  
 
 
3) required in-patient hospitalization (except for the implantation) or 
 
prolongation of existing hospitalization, or  
 
 
4) resulted in medical or surgical intervention to prevent permanent  
 
    impairment to body structure or a body function 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect.   
Explanatory note: an Adverse Event is considered Serious if condition 1, 2, 3, or 4 
apply in combination with a serious deterioration in health. E.g. a planned 
hospitalization for a pre-existing condition, without a serious deterioration in health is 
not considered to be a SAE. 
 
13.5 Serious Adverse Device Effect (SADE):  
An ADE that has resulted in any of the consequences characteristic of a Serious 
Adverse Event or that might have led to any of these consequences if suitable action 
had not been taken or intervention had not been made or if circumstances had been 
less opportune.  NOTE: the definition of SADE includes incidents and near incidents. 
 
13.6 Recording and reporting of AEs and device events 
Adverse Event (AE) information will be collected throughout the study and reported 
to the study coordinator on an Adverse Event Form. This Adverse Event form should 
be sent to the study coordinator. Contact details are given on page 1. All Adverse 
Events, regardless of relatedness or outcome, must be reported. 
Information reported on the Adverse Event Form shall include a description of the 
event, the date of event onset, the relatedness of the event to the procedure, the 
relatedness of the event to the device, actions taken as a result of the event, the 
outcome of the event, and the date the event was first noticed by the investigator. 
 
For Adverse Events that require immediate reporting (see table 1), initial reporting 
may be done by e-mail, or on the CRF completed as much as information is available, 
followed by the completed original adverse event form. 
All other AE’s must be reported in a timely manner. 
 

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13.7 Adverse Event review process 
All adverse events will be reviewed by the study coordinator. This review will include 
the determination whether the adverse event meets regulatory reporting requirements.  
 
Table 1: Adverse Event reporting requirements 
Serious Adverse Device Effects (SADE) 
Investigator submit to:  
PI/study coordinator 
Immediately after the investigator first learns of the event.  
MEC 
Reporting timeframe as per local MEC requirement.  
PI submit to: 
 
Regulatory Authorities  
Reporting timeframe as per local requirement. 
MEC 
Submit to MEC per local reporting requirement. 
 
13.8 Outcome 
The outcome of the AE should be classified according to the following definitions: 
• Ongoing: the event is ongoing and has not yet resolved. 
• Recovered / resolved: the event has resolved without sequelae (no further 
symptoms are present and no treatment is being received by the patient). 
• Recovered / resolved with sequelae: the event has resolved but there may be 
lingering effects present (e.g., a scar following a cut or abrasion). 
• Fatal: the patient died as a result of the event. This code should only be used 
for the event that caused the death, not any event that was present at the time 
of the patient’s death. Fatal events require immediately reporting to the 
sponsor (or an authorized representative). 
• Unknown: may only be used in the event that the patient is lost to follow-up 
and no reliable data can be obtained. 
All efforts should be made to classify the AE according to the above categories. 
 

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13.9 Follow-up of Adverse Events 
All AEs occurring during the study are to be followed up in accordance with good 
medical practice until resolved or judged no longer clinically significant, or if a 
chronic condition, until fully characterized. All follow-up results are to be reported in 
the eCRF. Assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the device, the interventions 
required to treat it, and the outcome. 
 
13.10 Patient Death 
All patient deaths during the investigation should be reported to the principal 
investigator within 24 hours.  
Notification of death should include a detailed statement of the pertinent events and 
be signed by the investigator or authorized personnel in addition to the appropriate 
CRF(s) (“Patient Death” and “Adverse Event” forms where applicable). It is the 
investigator’s responsibility to notify the appropriate Ethics Committees (EC). Details 
of death should be included in a letter to the principal investigator summarizing the 
patient’s course since enrolment in the study and the following information (Patient’s 
anonymity will be protected on all documents provided): 
• Date and time of death; 
• Place death occurred (e.g. hospital, nursing home, patient’s 
home); 
• Whether death was witnessed; 
• Cause of death (if known); 
• Any other circumstances surrounding the death; 
• Approximate time interval to death from the initiating 
event; 
• Whether it was device or procedure related; 
• Device configuration at time of death; 
• Autopsy report (if performed). 

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If available, also provide clinical notes and witness statements. All appropriate case 
report forms must be completed. 
 
14. Study Termination 
If a patient wishes to withdraw from the study at any time, he/she would be able to do 
so without having to justify it and without affecting his/her relationship with the 
investigator. Also, an investigator may withdraw a patient from the study at any time 
if he/she thinks it is in the patient’s best interest. In either case, the investigator will be 
requested to complete a “Termination Form” for any patient that leaves the study for 
whatever reason. 
 
15. Administrative Procedures 
15.1 Regulatory and ethical considerations 
This study will be conducted according compliance with the Declaration of Helsinki 
and national law.  
 
15.2 Informed Consent 
Before a patient can participate in the study, the patient must give written informed 
consent (witnessed, where required by law or regulation). The informed consent 
process will be in accordance with ISO 14155, the Declaration of Helsinki, the 
European Data Protection Directive and local regulatory requirements. Patient 
informed consent (PIC) forms will be based on a master document (see Appendix 
24.2), and must be submitted to the EC. Each potentially eligible patient will be 
informed of the study’s objectives and overall requirements. Prior to conducting any 
study-specific procedures, the investigator will explain the study fully to the patient. 
Patients will be informed that they take part in a study comparing different conditions 
of stimulation. If the patient is willing to participate in the study, he/she will be 
requested to give written informed consent after being given sufficient time to 
consider his/her participation and the opportunity to ask for further details. The PIC 

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will be signed and personally dated by both the patient and the investigator. A copy of 
the signed form will be provided to the patient, and the original will be retained with 
the source documents.  
 
15.3 Ethics Committee Requirements 
Before initiation of the study at a given site, approval of the protocol, PIC, and any 
information presented to potential patients must be obtained, in accordance with the 
declaration of Helsinki, from the appropriate EC. A signed and dated statement that 
the protocol and informed consent have been approved by the EC must be given to the 
coordinating clinical investigator before study initiation. This approval must include 
the protocol and informed consent versions numbers to ensure use of the approved 
study documents. If any amendments to any of these documents occur during the 
study, approval must be obtained prior to their implementation. The investigator is 
responsible for ensuring that these actions occur. The EC is required to keep the 
sponsor application for at least 3 years after the completion of the study. 
 
15.4 End of the Study 
For administrative and safety reporting purposes, the end of the study will be defined 
as the last visit of the last patient. This provides for a single and conservative 
definition across all study sites. 
 
15.5 Patient confidentiality 
The investigator must ensure that the patient’s anonymity is maintained. All data and 
measurements on participants in this trial will be entered via and managed by a secure 
data management application, ProMISe, of the department of Medical Statistics & 
BioInformatics of the LUMC. Data are accessible only via secure internet 
connections, using the Internet Explorer browser and access is limited to explicitly 
authorized users each of whom has his or her personal username and password. All 
access to the system is fully audited and logged and all changes can be traced back to 
their origin. The ProMISe system also performs routine quality checking and error 
reporting. The study coordinator has full access to the system. The randomisation 

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table is however fully shielded from all personnel except the trial statisticians and 
implanter/ case manager. ProMISe is a generic clinical data management system and 
extensively tested through its application in over 100 clinical registries and trials in 
Europe. Documents not for submission, such as signed PICs, should be maintained in 
strict confidence by the investigator. The sponsor will ensure that no patient will be 
identifiable either from the final report or published results. 
 
 
16. Statistical methods 
 
16.1 The aim of the study 
[1] to prove that the treatment has a beneficial effect over follow-up time since start of 
treatment 
[2] after [1] has been established,  to prove that there is a dose-response effect.  
 
While (1) may be ascribed (at least in part) to a placebo effect, we believe that (2) 
cannot, since its associated effect measure is based on a between group comparison 
with random allocation to which the patient should be sufficiently blinded. 
 
16.2 Endpoints 
The primary endpoint is the mean attack frequency (MAF). Let MAF0 and MAF6 
denote the MAF at baseline and the MAF at six months for a given patient.  MAF0 is 
the baseline value for each individual patient of the primary endpoint and hence will 
be taken into account in the analyses as a covariate; although the primary comparison 
is a randomised one and MAF0 strictly speaking does not need to be taken into 
account, incorporating this value into the analyses will increase power and allows 
secondary analyses with respect to possible interaction between the treatment and the 
baseline level. 
 
The MAF has a skewed distribution, and therefore we will take the (natural) logarithm 
in our analyses. If case MAF6 is equal to zero, we will add the minimal possible value 
of 0.25 (corresponding to a single attack per month) to allow taking the logarithm. 

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The analyses will take the general shape of a regression analysis with lnMAF6 as the 
dependent variable, lnMAF0 as the covariate and treatment as a fixed factor. An 
interaction between treatment and lnMAF0 will be added in a secondary analysis. 
 
We assume the following model:  lnMAF6= a +b*lnMAF0 + c*Treat, where Treat=0 
for 30% stimulation and Treat=1 for 100% stimulation, thus being an indicator 
variable for the randomly allocated arm. 
  
First we use an F test to evaluate (at the 5% level) the null-hypothesis 
 
(1) H01: a=0 & b=1 & c=0 
 
(effectively comparing this model to the null-model:  lnMAF6=lnMAF0 in both 
randomised groups) 
 
Rejection of this null-hypothesis means that we have confirmed a stimulation effect 
over time. Now, ONLY if (1) is rejected, do we test the following three null-
hypotheses 
 
(2a) H02a: a=0 & b=1 conditional on Treat=0 (30% stimulation) 
(2b) H02b: a=0 & b=1 conditional on Treat=1 (100% stimulation) 
(2c) H02c: c=0 (no stimulation intensity effect) 
 
Rejection of (2c) means that we have confirmed a dose-response effect, in other 
words a difference between 30% and 100% stimulation.  
 
16.3 Multi testing correction 
We claim that upon rejection of (1), we may simultaneously test (2a), (2b) and (2c) at 
the 5% level, while maintaining the probability of falsely rejecting a single null 
hypothesis at 5% (so without the need for correction for multiple testing). This 
follows from the so-called closed testing principle (42). The underlying idea is that if 
null hypothesis (1) is false, then at most one of (2a), (2b) and (2c) can be true. The 

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closed-testing principle has been applied before in clinical trials but not very often 
(43). The method is more powerful than the more familiar "gate keeping" procedure, 
where we test hypotheses (1), (2c), (2b) and (2a) in order, and stop as soon as we fail 
to reject one. 
  
The issue of multiple testing in biomedical research in general and in clinical trials in 
particular, is discussed by Bender and Lange (44). 
 
16.4 Power and sample size 
Because of limited information about the distribution of the MAF for our specific 
group of patients, we conducted a small pilot study. We found a MAF of 26.42 attacks 
per week, with a standard deviation of 15.38. These findings did not differ very much 
from figures given by Burns et al. (7).  These numbers correspond to lnMAF having a 
a mean of 3.13 and a standard deviation of 0.54. 
 
We expect (MAF6 – MAF0) to be -9 on average in the 100% stimulation group, while 
we expect no reduction in the 30% stimulation group. This corresponds to (lnMAF6 – 
lnMAF0) being -0.42 on average in the 100% stimulation group. 
 
If we assume that lnMAF0 and lnMAF6 are positively correlated, then the standard 
deviation of Delta = (lnMAF6-lnMAF0) would be in the range from 0.54 to √2 
*0.54=0.76. Powering in terms of this Delta is a fair approximation to the regression 
analysis model; in fact, if the coefficient b would be equal to 1, the calculations would 
be identical. 
 
Note that tests (1), (2a) and (2b) are in essence paired tests, comparing for each 
patient a change with respect to baseline. Test (2c) is an independent, two sample test 
because we compare the two treatment arms. Consequently, the test for (2c) will be 
the least powerful and so we performed our power analysis for that test. We did verify 
that all other tests are more powerful. 
 
We attach the results of our power analysis. We conclude that if the standard 
deviation is 0.54and the average of (lnMAF6-lnMAF0) is about -0.42,  then  60 

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patients in each arm will allow us to detect the difference with probability 98%. 
Taking a possible 20% drop-out rate into account, we propose a total study size of 144 
divided equally between both arms. 
 
 
 
16.5 Analyses 
We will use an intention to treat approach in all our primary analyses. A per protocol 
analysis will be undertaken if substantial deviations from the allocated treatment or a 
substantial amount of missing values are observed. In all cases the per protocol 
analyses will serve as a “sensitivity analysis” as intended by the ICH9 guidelines and 
a further support for proper interpretation of the ITT conclusions. 
 
Patients switching to steroids will be withdrawn from further data collection but are 
retained in the study as such. Their MAF will be included up to the time they started 
the new medication.  
 
Apart from the primary analyses which focus on a specific time point (6 months), 
secondary analyses will take the full repeated measurements structure into account, 
including the 6 months values. We use a mixed model for repeated measurements 
with time since randomisation as a fixed covariate (or factor), lnMAF0 as a 
randomisation 
100% stimulation
30% stimulation
Hypotheses 1: Group 30% and 100% 
versus baseline 
Hypotheses 2A: Group 30% 
versus baseline 
 
Hypotheses 2B: Group 100% 
versus baseline 
Hypotheses 2C: Group 30% 
versus group 100% 
 
6 months 
6 months 
  baseline 

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continuous covariate and Treat as a fixed factor. We will apply an AR1 covariance 
structure unless the data prove this to be untenable. This model is a direct extension of 
the simple regression model used to test the primary hypotheses and allows estimation 
of treatment effect over time, including possible interactions. We will also analyze the 
data using generalized estimating equations (GEE), aiming to consolidate the results 
from the mixed model analysis. 
 
The mixed model will take the missing values into account in a natural way, assuming 
of course missingness at random. A sensitivity analysis will be undertaken to verify 
this assumption. 
 
16.6 Randomisation and blinding 
Patients are randomised using a variable blocked stratified balanced design. The entire 
randomisation is generated before the first patient enters the trial and fixed. The 
randomisation table, although stored with the trial data base, is not accessible by users 
of the data management system except for the trial statistician and the implanter and 
casemanager. When a patient is entered into the (web based) data management 
system, the eligibility criteria are checked and the required stratification variables are 
specified. A request for randomisation is generated by the system and the next 
available record with the correct stratification values in the hidden randomisation 
table is allocated to the patient; both patient and randomisation record have a unique 
key which is stored both in the data tables and in the randomisation table. 
In the clinical data base the fact that the patient has been randomised, is made known 
by storing a random key which points to the record in the randomisation table. 
However, the web based interface does not allow any data manager or clinician to see 
the randomisation result if not authorized so by the very design of the trial. 
When the study data have to be analyzed according to randomised treatment, the 
randomisation table can be extracted from the data base by the statistician and joined 
to the clinical data extracted by the data manager of the trial. 
In case of emergency the statistician or implanter can either log on to the system and 
retrieve the randomisation of a patient via his (authorized) account or the 
randomisation table can be viewed directly in case the internet connections break 
down (but only from within the dep. of Medical Statistics). A backup of the 

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randomisation table is by definition assured since the entire data base is back up every 
day. 
 
 
 
17. Risk assessment 
 
ONS most important, known, related risks include: lead migration , low battery, neck 
stiffness (45). The risk of lead migration is probably related to the surgery technique 
used. In a recent Dutch study in 4 patients treated with ONS, there was no lead 
migration (unpublished data) or any other complications after 1.5 year follow-up. 
Other possible complications are unpleasant sensations of paraesthesias, haematoma, 
limited neck movements, skin discomfort, hardware failure (e.g. early end of life of 
the battery, which can cause sudden increase of headache) and infection. 
 
Treatment-as-usual related risks are related to the medication used and do not increase 
due to participation in this study. 
Until now, no persistent iatrogenic neurological deficit has been reported using ONS. 
 
Low Battery 
A low battery has to be surgically replaced. This will eventually occur in all patients, 
so it can be debated if an empty battery must be considered as a complication.  
 
18. Investigator / Site Selection 
18.1 Implantation site 
Site selection for implantation will be based on experience with and interest in ONS 
therapy for headache. Sites will be located in The Netherlands, UK and Denmark and 
probably Germany and Belgium. 
 
In order to qualify for participation in the study, sites are required to meet the 
following criteria:  

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1. Willing to comply with the Clinical Investigation Plan (CIP), all required 
procedures, the Declaration of Helsinki and local regulations 
2. Expertise in chronic pain treatment with ONS therapy and programming the 
stimulator 
3.  Availability of physician programmer (N’Vision) to adapt the ONS programming 
parameters 
 
18.2 Patient recruitment site 
Site selection for recruitment will be based on experience with treating CCH. Sites 
will be located in Europe. The investigator must have sufficient time to address the 
study requirements, reporting requirements and must have experience in patient 
selection and management. There must be a patient recruitment potential of at least 4 -
8 CCH patients/year for the trial. 
 
18.3 Training requirements 
The following will be addressed prior to site activation and throughout the study as 
needed: 
• Protocol specific training 
• Study training relevant and pertinent to the involvement of personnel 
conducting study activities, including investigator responsibilities 
• Product-specific information/device training 
• Specifics of study conduct 
• AE reporting 
The site and sponsor will maintain documentation of attendance at each of these 
training opportunities. 
 
 
19. Study Organization  
 
Study Management 

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The study will be managed and coordinated by the Leiden University Medical Centre, 
Leiden, The Netherlands. 
 
 
 
Study Investigators 
19.1 Principal Investigator 
 
 
Name 
Prof. Michel D. Ferrari MD, PhD 
 
 
Hospital 
Leiden University Medical Centre  
  
 
 
 
 
 
Department 
Neurology 
 
 
Address 
PO Box 9600 
 
 
City 
2300 RC Leiden 
 
 
Country 
The Netherlands 
 
 
Tel: 
+31-71-526-2895 
 
 
Fax: 
+31-71-52-8253 
 
19.2 Coordinating Clinical Investigator 
 
 
Name 
Patty G.G. Doesborg, MD 
 
 
Hospital 
Leiden University Medical Centre  
  
 
 
 
 
 
Department 
Neurology 
 
 
Address 
PO Box 9600 
 
 
City 
2300 RC Leiden 
 
 
Country 
The Netherlands 
 
Tel: 
+31-71-526-1645 
19.3 Amendment Procedure 
Any amendment to the Clinical Investigation Plan will be agreed by Coordinating 
Clinical Investigator and Principal Investigator prior to submission to Ethics 
Committee and Competent Authorities if applicable. 
19.4 Boards 
The Steering Committee will monitor the study and review its progress at regular 
intervals. Based on these reviews and Data Safety Monitoring Board (DSMB) 
outcomes, the Committee may request that the study be put on hold or even 
terminated for safety, ethical or other reasons. 

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An independent DSMB will be established prior to study enrolment and will have a 
minimum of three members with relevant expertise, and experience in clinical studies 
and/or as a DSMB member for another study. All members will lack significant 
conflicts of interest and one will be a biostatistician knowledgeable in the area of 
statistical methods used for clinical studies. One DSMB member with previous 
experience will be appointed as the chairperson. 
 
A DSMB Charter (or Manual of Operations) will be developed and agreed upon by 
the Sponsor and all DSMB members prior to the review of study related data. The 
Charter will describe its functions including, but not limited to, the following: 
 
• Meeting schedule and format 
• How the confidentiality/blinding of the data will be maintained 
• Who may attend all or part of the meetings 
• How conflicts of interest for potential committee members will be assessed 
• Timing and format for the presentation of data to the DSMB 
• How recommendations will be communicated to the Sponsor 
• Definition of a quorum 
• Interim and final analysis 
• Parameters for early termination 
• Procedures for documenting meeting minutes 
• Maintenance of relevant records 
 
The DSMB will receive summaries of adverse events reports on a bi-annual basis.  
The board may meet after bi-annual review, if they believe it is necessary.  However, 
the DSMB will be convened at least once a year, and additional meeting may be 
scheduled based on the accumulation rate of data on safety and effectiveness. 
 
20. Ethical Basis 
This study has been designed and shall be conducted according to the principles set in 
the Declaration of Helsinki 2008 revision and Good Clinical Practice (GCP)  
 

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Appropriate Ethics Committees approval for the study and the patient information 
sheet and consent form will be required prior to beginning the study. A copy of the 
approval is required by the LUMC prior to the first investigational product being 
implanted. 
 
21. Insurance / Indemnification  
Each participating centre maintains appropriate clinical trial liability insurance 
coverage as required under applicable laws and regulations and will comply with 
applicable local law and custom concerning specific insurance coverage. If required, a 
Clinical Trial insurance statement/certificate will be provided to the Ethics Committee 
for each individual participating recruitment or implantation centre. Indemnification 
statements will be provided as required per regulations. 
 
22. Publication Policy 
This study will be registered in a secured database in accordance with the Declaration 
of Helsinki, and data resulting from the study will be made publicly available. It is 
anticipated that at least one publication will be generated from the study results, to be 
published in a peer reviewed journal. The principle investigators will have access to 
all cleaned study data and can use it for scientific purposes. The investigators can 
propose projects to the principle investigators using the database.  
 
With respect tot publication policy, the following aspects will be addressed: 
1. All study results will be published without restrictions. This means that 
patients are entitled to the right that the study results will be published, based 
on their participation in the study.  
2. All members of the study group agree that all study results will be published.   
3. Both negative and positive results will be published. 
4. Before publication, all authors will have the opportunity to give comments on 
the manuscript.  
5. Data will be published as soon as possible after finishing data analysis.  
 
Specific details will be described in a separate publication plan, which will be 
provided to investigators for review and agreement. 
 

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23. Study reimbursement 
This study is funded by Medtronic with an unrestricted grant. The salary of the 
coordinating clinical investigator only is paid from this grant. Since 2013 Medtronic 
is willing to deliver the needed occipital nerve stimulation devices for the participants 
within the study, if this is not covered by their health insurance. After expiration or 
termination of the Research Agreement, Medtronic shall, pending approval through 
Medtronic's established internal process, provide replacement Devices until either: 
Medtronic no longer manufactures the Devices, the therapy/ devices (their 
components) has/have obtained Reimbursement or the ICON patient is no longer 
receiving benefit from the Devices, whichever occurs first. Medtronic has no 
influence on the study design, analysis or publication of the data. Dr. R. Buschman, 
department of Benelux and Nordic region, Medtronic, is a non-voting observing 
member of the Steering Committee. 
 
24. Appendices 
 
 
24.1 
 
Case report forms 
 
24.2 
 
Informed consent 
 
 
 
 

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Protocol: Occipital nerve stimulation in medically intractable, chronic cluster headache 
CME Protocol number: 10.016 
Version 1.11 dd. 26-09-2018 
 
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