IIH Provoke
Calcitonin gene-related peptide induces headache attacks in people with idiopathic intracranial hypertension
Bottom Line
IV CGRP triggered typical IIH headache attacks in 71% vs 18% with placebo (P=0.004) and increased ICP pulse amplitude without changing mean ICP, supporting a CGRP-mediated mechanism for IIH headache and justifying trials of CGRP-pathway blockade.
Major Points
- First human provocation trial testing CGRP as a trigger for IIH headache — 20-min CGRP infusion (1.5 μg/min) provoked typical IIH headache with migraine-like features in 71% of participants vs 18% with placebo (P=0.004).
- Novel finding: CGRP increased ICP pulse amplitude (measure of intracranial compliance) without changing mean ICP — links vascular signalling to symptom generation in a secondary headache disorder.
- Cerebrovascular signature matched prior migraine provocation studies: ↑ HR, ↑ oxygenated haemoglobin, ↑ tissue oxygenation, ↓ MAP, ↓ MCA velocity — consistent with vasodilation.
- Provides mechanistic rationale for prospective evaluation of CGRP monoclonal antibodies / gepants in IIH-related headache, an area with no approved targeted therapy.
- Small sample (n=17) at a single centre and women-only cohort limits generalisability; findings need replication and translation into a therapeutic trial.
Design
Study Type: Randomized, double-blind, placebo-controlled, two-way crossover provocation trial
Randomization: 1
Blinding: Double-blind (participant and investigators masked; independent CRF staff prepared/administered drug)
Enrollment Period: February 2023 to May 2024
Follow-up Duration: 12 h post-infusion observation per visit; visits ≥6 days apart
Centers: 1
Countries: United Kingdom
Sample Size: 20
Analysis: 17 completed both visits and were included in the analysis; block randomization (blocks of 4) for treatment order
Registration: ISRCTN13251508
Inclusion Criteria
- Women aged 18-60 years
- Previous diagnosis of IIH per revised diagnostic criteria
- Headache attributed to IIH per ICHD-3B
- Ongoing papilloedema (OCT peripapillary RNFL ≥109 μm in one/both eyes or specialist-confirmed active IIH) OR IIH in ocular remission
- Able to give informed consent
- Where possible, participants with in-situ telemetric ICP monitor were preferentially recruited
Exclusion Criteria
- Previous migraine history prior to IIH diagnosis
- Non-IIH headache >1 day per month
- Pregnancy or trying to conceive
- Significant medical co-morbidity
- Known cardiovascular or cerebrovascular disease
- Medication overuse
- Functioning dural venous stent, or CSF shunt with no programmable valve, or optic nerve sheath fenestration
- Currently using GLP-1 receptor agonist or DPP-4 inhibitor
Arms
| Field | CGRP | Control |
|---|---|---|
| Intervention | Continuous IV infusion of α-CGRP 1.5 μg/min for 20 min | Continuous IV infusion of isotonic saline for 20 min |
| Duration | 20 min infusion; 12 h observation | 20 min infusion; 12 h observation |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Difference in proportion of participants developing a provoked IIH headache attack (with migraine-like features) during 12 h after infusion | Primary | 0.004 | |||
| AUC of headache intensity (−10 min to 12 h), median (IQR) | Secondary | 1800 (95-2423) | 0.016 | ||
| Peak headache severity NRS, median (IQR) | Secondary | 6.5 (4.8-8) | 0.020 | ||
| Median (IQR) onset time of provoked attack (min) | Secondary | 90 (35-285) (n=12) | 0.109 | ||
| Headache worse with activity / kinesiophobia | Secondary | 59% (10) | 0.023 | ||
| Photophobia | Secondary | 65% (11) | 0.023 | ||
| Heat sensation | Secondary | 94% (16) | <0.001 | ||
| Flushing / facial redness | Secondary | 76% (13) | 0.002 | ||
| Palpitations | Secondary | 59% (10) | 0.004 | ||
| Nausea | Secondary | 47% (8) | 0.074 | ||
| Heart rate AUC−10min-90min (bpm·min, SD) | Secondary | 1448 (544.3) | <0.001 | ||
| MAP AUC−10min-90min (mmHg·min, SD) | Secondary | 836.8 (460.6) | 0.01 | ||
| MCA blood velocity AUC−10min-90min | Secondary | 371.5 (210.0) | 0.006 | ||
| Oxygenated haemoglobin AUC−10min-90min | Secondary | 17 853 (6128) | <0.001 | ||
| Tissue oxygenation index AUC−10min-90min | Secondary | 248.4 (156.7) | 0.041 | ||
| ICP amplitude AUC−10min-90min (cm H2O·min, SD) | Secondary | 140.1 (42.5) (n=8) | 0.005 | ||
| Mean ICP AUC−10min-90min | Secondary | 144.3 (110.0) | 0.999 | ||
| Study drug tolerability | Adverse | Continuous IV infusion completed by 17/17 in the analysed cohort. Provocation elicited expected CGRP-related events — flushing (76%), heat sensation (94%), palpitations (59%). No pathological ICP waveforms observed. No serious adverse events reported in the primary paper. | |||
| Withdrawals | Adverse | 3 of 20 randomized discontinued before receiving study drug (1 withdrew for non-safety reason; 2 lost to contact). | |||
Subgroup Analysis
All 4 participants with a family history of migraine had CGRP-provoked headache but none after placebo. Active IIH (papilloedema, n=9): CGRP 67% vs placebo 11%. Ocular remission (n=8): CGRP 75% vs placebo 25%. Biphasic headache course after CGRP in 9 participants (early peak median 30 min, delayed peak median 300 min).
Criticisms
- Small single-centre sample (n=17 completers) and women-only cohort — replication in men and multi-centre samples needed.
- Selected participants with no prior migraine history to isolate IIH mechanism, which excludes the many IIH patients who have coexisting migraine and may most benefit from CGRP blockade.
- Provocation model demonstrates a causal signal but does not directly show that CGRP-pathway blockade prevents spontaneous IIH headache — therapeutic RCT still required.
- ICP monitoring only available in the 13 participants with in-situ telemetric shunts; ICP amplitude analyses based on n=8 per arm — modest precision.
- 12-hour observation may miss delayed effects, and participants were kept in a semi-recumbent position for the entire recording period, which may attenuate positional headache features.
Funding
Details in full paper. Independent Clinical Research Facility staff prepared, allocated and administered the study drug. Multiple UK academic and NHS affiliations (University of Birmingham, University Hospitals Birmingham NHSFT, Danish Headache Centre).
Based on: IIH Provoke (Brain, 2026)
Authors: Yiangou A, Do TP, Mollan SP, ..., Sinclair AJ
Citation: Brain 2026;149(8):2629-2642
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