Occipital Blocks for Acute Migraine

Phase 3

Completed

Conditions: Chronic Migraine, Headache
Episodic Migraine

Interventions: Drug: Lidocaine 4% Topical Application Cream [LMX 4]
Drug: Lidocaine Hydrochloride 2 mg/mL Injectable Solution
Drug: Normal Saline

Registration Number: NCT03526874

Lead Sponsor: Children's Hospital of Philadelphia

Brief Summary: Migraine affects 10-28% of children and adolescents and yet 20-30% of patients are ineffectively treated with current oral and nasal options. Peripheral nerve blocks (PNBs), injections of local anesthetics over branches of the occipital and/or trigeminal nerves, have been associated with possible benefit for pediatric headaches in case series, and may be useful for both acute and preventive treatment of migraine for children who fail less invasive treatments. In fact, 80% of pediatric headache specialists reported using peripheral nerve blocks and carry low risk of serious side effects; however, peripheral nerve blocks have never been tested, formally, in a randomized pediatric trial.

By applying a novel design that utilizes lidocaine cream as a run-in step, investigators intend to test the efficacy of the most commonly used peripheral nerve block, the greater occipital nerve (GON) block, as an acute treatment for pediatric migraine and determine whether lidocaine cream leads to successful blinding of the injection.

The GON block is expected to prove effective in decreasing the pain of migraine, with lidocaine being superior to saline and lidocaine cream maintaining blinding.

Detailed Description: There are two substantial hurdles that must be overcome in designing a trial to test the efficacy of PNBs: high placebo response rate and possible unblinding. In order to test the efficacy of this commonly used treatment for children and adolescents with difficult-to-treat headache, we need utilize a trial design which will address the high placebo response rate and the potential lack of blinding.

About 194 children, recruited over a 3.5 year period at Children's Hospital of Philadelphia, will take part in this study. Participation will last about one month and involve one in-person study visit, and then completion of headache-related surveys, at home, for 28 days. Lidocaine cream lead-in will be used open-label for all subjects followed by double-blind randomized injections of active treatment (lidocaine) versus comparator (saline) in subjects who continue to have significant headache.

To accomplish our secondary objectives, we will examine how expectation is affected by perceived treatment, and how expectations, measured in patients, parents, and providers, influence outcomes in pediatric and adolescent acute migraine.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 63

Inclusion Criteria

Children / Adolescents:
- Males or females, ages 7 - 21, of any gender, race, or ethnicity
- Diagnosis of episodic or chronic migraine with acute headache flare lasting up to 3 months unresponsive to acute medications. Patients who report that acute medications were not used during this headache flare because those medications have been ineffective for several prior headache flares will be included
- Informed parental consent and subject assent
- Girls, who have reached menarche, must have a negative urine or serum pregnancy test
- Weight > 25kg
Parents:
- Parents or guardians of children enrolled, who speak either English or Spanish, and provide parental/guardian permission (informed consent) for their own participation
- Subject (child) assent

Exclusion Criteria

Children / Adolescents:
- Previous nerve block less than 3 months ago or more than 2 previous nerve blocks
- Allergy to local anesthetics
- Skull defect or break in the skin at the planned site of cream application or GON injection
- Any investigational drug use within 30 days prior to enrollment, or 90 days prior to enrollment for medications targeted at Calcitonin Gene-Related Peptide
- Pregnant or lactating females
- Parents/guardians or subjects who, in the opinion of the Investigator, may be non- compliant with study schedules or procedures
- Significant adverse event with prior injection or procedure
- New abnormalities on physical or neurological examination
- Newly reported red flags in headache history which prompt investigation for secondary headache
- Non-English and Non-Spanish speaking
- Non-English speaking with no Spanish interpreter available
Parents:
- Parents or guardians of children enrolled, who do not speak either English or Spanish
- Parental/guardian permission and/or subject (child) assent has been declined
- Parents or guardians, who in the opinion of the investigator, may be non-compliant or unable to complete the questionnaires

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Greater Occipital Nerve (GON) Block with Lidocaine	Lidocaine Hydrochloride 2 mg/mL Injectable Solution	Subjects randomized to this arm receive 2 mL injection of lidocaine 2% over the right and left greater occipital nerve at the baseline study visit. All subjects then complete daily headache-related questions through a Headache Diary and other assessments for 28 days.
Greater Occipital Nerve (GON) Block with Lidocaine	Lidocaine 4% Topical Application Cream [LMX 4]	Subjects randomized to this arm receive 2 mL injection of lidocaine 2% over the right and left greater occipital nerve at the baseline study visit. All subjects then complete daily headache-related questions through a Headache Diary and other assessments for 28 days.
Greater Occipital Nerve (GON) Block with Saline	Lidocaine 4% Topical Application Cream [LMX 4]	Subjects randomized to this arm receive 2 mL injection of preservative-free normal saline over the right and left greater occipital nerve at the baseline study visit. All subjects then complete daily headache-related questions through a Headache Diary and other assessments for 28 days.
Greater Occipital Nerve (GON) Block with Saline	Normal Saline	Subjects randomized to this arm receive 2 mL injection of preservative-free normal saline over the right and left greater occipital nerve at the baseline study visit. All subjects then complete daily headache-related questions through a Headache Diary and other assessments for 28 days.

Primary Outcome Measures

Name	Time	Method
Mean Change in Pain Intensity Scores Measured by the Numeric Analog Scale (NRS)	Pre-injection (Baseline) and 30 minutes Post-injection	By subtracting the 30 minutes post-injection score from the pre-injection score, measured on a Numeric Rating Scale (NRS), the mean change, in the lidocaine versus saline groups, will be used as the primary outcome measure. NRS scale is a 0 to 10 scale, with 0 meaning no pain and 10 meaning "the worse pain imaginable". A mean change of 2-points has been shown to be clinically relevant.
Mean Change in Pain Intensity Scores Measured by the Visual Analog Scale (VAS)	Pre-injection and 30 minutes Post-injection	By subtracting the 30 minutes post-injection score from the pre-injection score, measured on a Visual Analog Scale (VAS), the mean change, in the lidocaine versus saline groups, will be used as the primary outcome measure. VAS scale is a 0 to 100 visual scale, with 0 meaning no pain and 100 meaning "the worse pain imaginable".
Mean Change in Pain Intensity Scores Measured by the Numeric Analog Scale (NRS) by Sex	Pre-injection (Baseline) and 30 minutes Post-injection	By subtracting the 30 minutes post-injection score from the pre-injection score, measured on a Numeric Rating Scale (NRS), the mean change, in the lidocaine versus saline groups, will be used as the primary outcome measure. By sex. NRS scale is a 0 to 10 scale, with 0 meaning no pain and 10 meaning "the worse pain imaginable". A mean change of 2-points has been shown to be clinically relevant.
Mean Change in Pain Intensity Scores Measured by the Visual Analog Scale (VAS) by Sex	Pre-injection and 30 minutes Post-injection	By subtracting the 30 minutes post-injection score from the pre-injection score, measured on a Visual Analog Scale (VAS), the mean change, in the lidocaine versus saline groups, will be used as the primary outcome measure. By sex. VAS scale is a 0 to 100 visual scale, with 0 meaning no pain and 100 meaning "the worse pain imaginable".
Mean Change in Pain Intensity Scores Measured by the Numeric Analog Scale (NRS) by Ethnicity	Pre-injection (Baseline) and 30 minutes Post-injection	By subtracting the 30 minutes post-injection score from the pre-injection score, measured on a Numeric Rating Scale (NRS), the mean change, in the lidocaine versus saline groups, will be used as the primary outcome measure. By ethnicity. NRS scale is a 0 to 10 scale, with 0 meaning no pain and 10 meaning "the worse pain imaginable". A mean change of 2-points has been shown to be clinically relevant.
Mean Change in Pain Intensity Scores Measured by the Visual Analog Scale (VAS) by Ethnicity	Pre-injection and 30 minutes Post-injection	By subtracting the 30 minutes post-injection score from the pre-injection score, measured on a Visual Analog Scale (VAS), the mean change, in the lidocaine versus saline groups, will be used as the primary outcome measure. By ethnicity. VAS scale is a 0 to 100 visual scale, with 0 meaning no pain and 100 meaning "the worse pain imaginable".
Mean Change in Pain Intensity Scores Measured by the Numeric Analog Scale (NRS) by Race	Pre-injection (Baseline) and 30 minutes Post-injection	By subtracting the 30 minutes post-injection score from the pre-injection score, measured on a Numeric Rating Scale (NRS), the mean change, in the lidocaine versus saline groups, will be used as the primary outcome measure. By race. NRS scale is a 0 to 10 scale, with 0 meaning no pain and 10 meaning "the worse pain imaginable". A mean change of 2-points has been shown to be clinically relevant.
Mean Change in Pain Intensity Scores Measured by the Visual Analog Scale (VAS) by Race	score on a scale	By subtracting the 30 minutes post-injection score from the pre-injection score, measured on a Visual Analog Scale (VAS), the mean change, in the lidocaine versus saline groups, will be used as the primary outcome measure. By race. VAS scale is a 0 to 100 visual scale, with 0 meaning no pain and 100 meaning "the worse pain imaginable".

Secondary Outcome Measures

Name	Time	Method
Change From Baseline Disability to Day 7	Baseline and Day 7	The Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference (Short Form) will assess changes in functional disability due to headache. The PROMIS Pain Interference (Short Form) measures the self-reported consequences of pain on relevant aspects of the subject's life over the past seven days. A pain item pool was developed to yield scores on a T-score scale with a mean of 50 and standard deviation of 10. A higher PROMIS T-score represents more pain interference, a T-score of 60 is one standard deviation (SD) worse than average. By comparison, a pain interference T-score of 40 is one SD better than average.
Percentage of Subjects With Sustained Pain Relief	24 hours Post-injection	The measurement involves having pain-relief within 30 minutes and lasting at least 24 hours, with no use of rescue medication and no relapse or recurrence. Data will be collected prospectively from subjects, via text, in an electronic headache diary.
Percentage of Subjects With Pain Freedom	30 minutes Post-injection	The measurement involves resolution of headache pain within 30 minutes after injection and prior to any rescue medications. Data will be collected prospectively from subjects, at the study visit.
Percentage of Subjects With Sustained Pain Freedom	24 hours Post-injection	The measurement involves being pain-free within 30 minutes and lasting at least 24 hours, with no use of rescue medication and no relapse or recurrence. Data will be collected prospectively from subjects, via text, in an electronic headache diary.
Percentage of Subjects With Freedom From All Symptoms of Migraine	24 hours Post-injection	The presence or absence of photophobia, phonophobia, and nausea will be collected from subjects prospectively, via text, in an electronic headache diary.
Change From Baseline Disability to Week 4	Baseline and Week 4	The PROMIS Pain Interference (Short Form) will assess changes in functional disability due to headache. The PROMIS Pain Interference (Short Form) measures the self-reported consequences of pain on relevant aspects of the subject's life over the past seven days. A pain item pool was developed to yield scores on a T-score scale with a mean of 50 and standard deviation of 10. A higher PROMIS T-score represents more pain interference, a T-score of 60 is one SD worse than average. By comparison, a pain interference T-score of 40 is one SD better than average.
Change From Baseline Disability	Baseline and Week 4	The PedMIDAS will assess changes in functional disability due to headache. The PedMIDAS is a validated 6-question scale that captures headache-related disability-across multiple domains of functioning including school, home, social, and recreational-for pediatric and adolescent aged patients over 3 months. The instrument measures the number of days in which subjects missed activities due to headache or migraine. The measure yields a total score by summing items ranging from 0 to 90 day. The higher the score the higher the disability. Change in total score (total at week 4 minus total at baseline) is reported.
Percentage of Subjects With Pain Relief or Headache Response	30 minutes Post-injection	The measurement involves improvement in headache from "severe or moderate" to "none or mild" within 30 minutes and before any rescue medications. Data will be collected prospectively from subjects at the study visit.