Occipital Nerve Stimulation in Medically Intractable Chronic Cluster Headache

NCT01151631 | Completed Phase 3 DMC

• 1 other identifier: ICON-01
• Study Type: interventional
• Target: 130
• Locations: 4 countries
• Sites: 7

Brief 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. 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. 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 the investigators 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 and whether patients would recommend the treatment to another patient. The investigators will also investigate whether predictive factors can be identified for efficacy.

Conditions

Chronic Cluster Headache

Outcome Measures

Primary Outcomes (1)

• The mean attack frequency (MAF) over the last 4 weeks in the 100% and the 30% treatment groups

  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.

  6 months

Secondary Outcomes (11)

• The MAF during follow up

  for each 4 week period of the whole follow-up period

• The mean attack intensity (on a scale from 0-10) will be calculated and will be compared between and within the 2 groups.

  over the last 4 weeks for each group at baseline, 6 and 12 months follow up

• Rate of responders (>50% reduction in attack frequency in the last 4 weeks compared to baseline) will be calculated and compared between groups

  6 and 12 months follow up

• Economic evaluation

  baseline and 6 months follow-up

• Anticipated group randomisation

  at 12 months follow-up

Study Arms (2)

100% occipital nerve stimulation

ACTIVE COMPARATOR

Stimulation frequency and pulse width will be uniformly held constant at 60 Hz and pulse width at 450 ms. The perception and discomfort amplitude will be defined by increasing the stimulation amplitude in steps of 0.1 V. The amplitude at which the patient starts feeling paraesthesis 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.

Device: occipital nerve stimulation

30% occipital nerve stimulation

SHAM COMPARATOR

30% stimulation means a stimulation level at 30% of the range between perception threshold and 100% stimulation level

Device: occipital nerve stimulation

Interventions

occipital nerve stimulation DEVICE

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

Also known as: Versitrel™, Pisces Quad® Plus, Versitrel™ Patient Programmer

100% occipital nerve stimulation; 30% occipital nerve stimulation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \* Diagnosis of patients with CH shall be in accordance with The International Classification of Headache Disorders, 2nd Edition:
• 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:
• ipsilateral conjunctival injection and/or lacrimation
• ipsilateral nasal congestion and/or rhinorrhoea
• ipsilateral eyelid oedema
• ipsilateral forehead and facial sweating
• ipsilateral miosis and/or ptosis
• 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
• 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 refrain from starting new prophylactic CH medication, including steroids, or any other therapy aimed at CH and agrees to maintain existing prophylactic CH medication from 4 weeks before entering the baseline 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.

You may not qualify if:

• Other significant neurological or disabling diseases 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 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
• Enrollment 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

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Maastricht University Medical Center: collaborator
• Erasmus Medical Center: collaborator
• Technical University of Twente: collaborator
• Canisius-Wilhelmina Hospital: collaborator
• University of Copenhagen: collaborator
• University Hospital, Ghent: collaborator
• Royal Free Hospital NHS Foundation Trust: collaborator
• Medtronic: collaborator
• Centre Hospitalier Régional de la Citadelle: collaborator
• Schmerzklinik Kiel: collaborator
• University Hospital Schleswig-Holstein: collaborator
• National Institute of Neuroscience, Budapest: collaborator

Study Sites (7)

CHR La Citadelle hospital

Liège, Belgium

Location

Schmerzklinik Kiel

Kiel, D-24149, Germany

Location

National Institute of Neuroscience

Budapest, Hungary

Location

Boerhaave MC

Amsterdam, Netherlands

Location

Atrium medical centre

Heerlen, 6417, Netherlands

Location

Leiden University Medical Center

Leiden, 2333 ZA, Netherlands

Location

Canisius Wilhelmina Hospital

Nijmegen, 6532 SZ, Netherlands

Location

Related Publications (5)

• Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology. 2009 Jan 27;72(4):341-5. doi: 10.1212/01.wnl.0000341279.17344.c9.

  PMID: 19171831 BACKGROUND

• Burns B, Watkins L, Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: long-term follow-up of eight patients. Lancet. 2007 Mar 31;369(9567):1099-106. doi: 10.1016/S0140-6736(07)60328-6.

  PMID: 17398309 BACKGROUND

• Magis D, Allena M, Bolla M, De Pasqua V, Remacle JM, Schoenen J. Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol. 2007 Apr;6(4):314-21. doi: 10.1016/S1474-4422(07)70058-3.

  PMID: 17362835 BACKGROUND

• Brandt RB, Mulleners W, Wilbrink LA, Brandt P, van Zwet EW, Huygen FJ, Ferrari MD, Fronczek R; ICON study group. Intra- and interindividual attack frequency variability of chronic cluster headache. Cephalalgia. 2023 Feb;43(2):3331024221139239. doi: 10.1177/03331024221139239.

  PMID: 36739508 DERIVED

• Wilbrink LA, de Coo IF, Doesborg PGG, Mulleners WM, Teernstra OPM, Bartels EC, Burger K, Wille F, van Dongen RTM, Kurt E, Spincemaille GH, Haan J, van Zwet EW, Huygen FJPM, Ferrari MD; ICON study group. Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): a randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial. Lancet Neurol. 2021 Jul;20(7):515-525. doi: 10.1016/S1474-4422(21)00101-0.

  PMID: 34146510 DERIVED

MeSH Terms

Conditions

Cluster Headache

Condition Hierarchy (Ancestors)

Trigeminal Autonomic Cephalalgias; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Michel Ferrari, MD PhD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. M.D. Ferrari, MD PhD

Study Record Dates

• First Submitted: June 24, 2010
• First Posted: June 28, 2010
• Study Start: October 1, 2010
• Primary Completion: September 1, 2018
• Study Completion: March 1, 2019
• Last Updated: February 28, 2020

Record last verified: 2020-02

Locations

HU (1); DE (1); BE (1); NL (4)