Treatment of Chronic Cluster Headache With TENS and ONS

Study Overview
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Brief Summary
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The study is an investigator-initiated, prospective, randomized, placebo-controlled, double blind clinical trial that aims to investigate the effect of transcutaneous electrical nerve stimulation (TENS) and occipital nerve stimulation (ONS) on attack frequency and severity in patients with chronic cluster headache (CH). Study outline Month 1: Baseline. Establishment of a baseline profile of the participants CH attacks (severity, duration, medicine utilization etc), health-related quality of life (QoL) and symptoms of anxiety and depression. No active treatment. Follow-up visit after 30 days. Months 2-4: TENS period. All participants will receive TENS-treatment. Clinical follow-up visit by the end of month four. Months 5-7: Double-blinded, randomized experimental period. All participants will have an ONS-system (lead, impulse generator) implanted and will be randomized 1:1 to receive either 1) burst (paresthesia-free) ONS or 2) placebo (deactivated ONS system). Clinical follow-up visit by the end of month seven. Months 8-10: Open label period. All participants will receive tonic (conventional, paresthesia-inducing) ONS. Clinical follow-up visit by the end of month ten. During every study phase each participant will fill out a weekly electronic headache registration as well as answering questionnaires regarding health-related quality of life and symptoms of anxiety and depression before every follow-up visit.

Official Title
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Treatment of Chronic Cluster Headache (Horton's Headache) With Transcutaneous Electrical Nerve Stimulation and Occipital Nerve Stimulation

Conditions
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Primary Headache Disorder, Chronic Cluster Headache, Headache, Cluster Headache, Pain, Cephalgia, Trigeminal Autonomic Cephalgia

Intervention / Treatment
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* Device: Paresthesia-free (burst) ONS
* Device: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years and above Signed informed written consent Diagnosed with chronic CH according to the ICHD-3 criteria 15 or more CH attacks per month Stable use of preventive headache medication one month prior to enrollment Exclusion Criteria: Other ongoing neuromodulation therapy Current alcohol and/or drug abuse Severe psychiatric disorder Other chronic primary or chronic secondary headache disorder (e.g. chronic migraine) Major posterior neck surgery in C2-C3 level and above Pregnancy Treatment with oral steroids or GON injection within one month of study participation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Paresthesia-free (burst) ONS<br>Implanted lead and impulse generator (IPG), paresthesia-free (burst) active stimulation. Lead implanted subcutaneously over greater occipital nerves. Implanted IPG capable of providing paresthesia-free stimulation continuously. | Device: Paresthesia-free (burst) ONS<br>* Stimulation intensity target of 60% of paresthesia threshold.<br>|
| Placebo Comparator: Placebo<br>Implanted lead and IPG, deactivated. | Device: Placebo<br>* ONS system deactivated<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30% reduction in CH attack frequency with TENS- and ONS-treatment | Proportion of participants with a positive treatment outcome of a 30% reduction in CH attack frequency compared to baseline. A CH attack is here defined as any attack recognised by the patient as a CH attack. | Primary evaluation through month 4 (TENS) and 7 (ONS, blinded) | 
| Incidence of treatment-emerged adverse events [safety] in TENS treatment | Treatment related adverse events and adverse device effects will be registered on an ongoing basis. Serious events will be handled immediately. | Evaluation at month 4 | 
| Incidence of treatment-emerged adverse events [safety] in ONS treatment | Treatment related adverse events and adverse device effects will be registered on an ongoing basis. Serious events will be handled immediately. | Evaluation at month 7 (burst ONS) and 10 (tonic ONS) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30% reduction of pain intensity in CH attacks | Weekly self reported pain intensity on a numeric rating scale from 0-10 with 0 being no pain and 10 the worst possible pain. Proportion of participants with a positive treatment outcome of a 30% reduction in pain intensity during CH attacks compared to baseline. | Through month 4, 7 and 10 | 
| Feasibility of TENS as a predictor for the efficacy of ONS treatment | Comparison will be made of headache data from the last month of treatment with TENS and tonic ONS, respectively, to evaluate whether a 30% reduction in CH attack duration with TENS-treatment correlates to a 30% reduction in CH attack duration with ONS-treatment. | Through month 4 and 10 | 
| Non-inferiority study: Burst ONS versus tonic ONS | Comparing treatment outcome of burst ONS and tonic ONS. | Through month 7 and 10 | 
| Patient-perceived Global Impression of Change (PGIC) | The number of participants who rates their condition 'much improved' or 'very much improved' as assessed by PGIC. | At month 4, 7 and 10 | 
| Reduction in background headache | Proportion of participants reporting a reduction in background headache. A positive treatment outcome will be defined as a two-point improvement on a four-point scale compared to baseline. | At month 4, 7 and 10 | 
| Hospital anxiety and depression scale (HADS) | HADS is a self-assessment questionnaire consisting of seven items each for depression and anxiety sub-scales. Scoring for each item ranges from zero to three, with three denoting highest anxiety or depression level. HADS score will be evaluated at every follow up and compared to baseline. | At month 4, 7 and 10 | 
| Health-related quality of life (EuroQoL 5D-5L) | The EQ 5D-5L is a well-established measure of health-related quality of life that is quantified as a utility (a measure of quality of life between 0 and 1) based on a danish value set. Furthermore a total score that ranges from 0-100 (visual analog scale), a higher score indicates better health-related quality of life. | At month 4, 7 and 10 | 
| Self reported sleep quality | Proportion af participants reporting a positive treatment outcome defined as a two-point improvement on a four-point scale compared to baseline. | At month 4, 7 and 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Occipital nerve stimulation, Neuromodulation, Transcutaneous electrical nerve stimulation