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PROMISE-2

Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2

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Year of Publication: 2020

Authors: Richard B. Lipton, Peter J. Goadsby, Jeff Smith, ..., Roger Cady

Journal: Neurology

Citation: Neurology. 2020;94:e1365-e1377. doi:10.1212/WNL.0000000000009169

Link: https://pubmed.ncbi.nlm.nih.gov/32209650/

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PM...Y2019981969.pdf

Clinical Question

Does intravenous eptinezumab, a humanized anti-CGRP monoclonal antibody, demonstrate efficacy and safety in the preventive treatment of chronic migraine compared to placebo?

Bottom Line

In patients with chronic migraine, intravenous eptinezumab 100 mg and 300 mg demonstrated significant reduction in monthly migraine days from the day after IV administration through week 12, was well tolerated, and had an acceptable safety profile with preventive effects observed as early as day 1 after administration

Major Points

  • First phase 3 trial evaluating IV eptinezumab (anti-CGRP mAb) for chronic migraine prevention
  • Both doses achieved primary endpoint: significant reduction in MMDs over weeks 1-12 (100 mg: -7.7 days, 300 mg: -8.2 days vs placebo -5.6 days, p<0.0001)
  • Rapid onset of action: preventive effect observed on day 1 after first IV administration with >50% reduction in migraine incidence
  • Day 1 migraine prevalence: 28.6% (100 mg) and 27.8% (300 mg) vs 42.3% (placebo), p<0.0001 for both doses
  • High responder rates: ≥75% responder rate at weeks 1-12 was 26.7% (100 mg) and 33.1% (300 mg) vs 15.0% (placebo)
  • ≥50% responder rate weeks 1-12: 57.6% (100 mg) and 61.4% (300 mg) vs 39.3% (placebo), p<0.0001
  • Significant reduction in acute medication use: 100 mg -3.3 days, 300 mg -3.5 days vs placebo -1.9 days (p<0.0001 for 300 mg)
  • Significant improvement in HIT-6 scores at week 12: 300 mg -2.9 difference from placebo (p<0.0001)
  • Well-tolerated safety profile: TEAEs similar across groups (100 mg 43.5%, 300 mg 52.0%, placebo 46.7%)
  • 93.6% of patients completed study through week 12; 95.5% of 100 mg and 96.6% of 300 mg patients received both doses

Design

Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study

Randomization: 1

Blinding: Double-blind; patients, investigators, clinicians, and research personnel remained blinded throughout study; assignment concealed; double-dummy design with matching placebo; independent project nurse conducted randomization

Enrollment Period: November 30, 2016 to April 20, 2018 (last patient last visit)

Follow-up Duration: 32 weeks total (28-day screening, 24-week double-blind treatment phase, 4-week safety follow-up); primary efficacy period through week 12

Centers: 128

Countries: United States, Spain, Ukraine, Russian Federation, United Kingdom, Republic of Georgia, Hungary, Italy, Slovakia, Germany, Czech Republic, Denmark, Belgium

Sample Size: 1072

Analysis: Full analysis set (FAS) and safety analysis set (SAF) included all randomized patients receiving ≥1 dose; patients analyzed by randomized treatment in FAS, by actual treatment received in SAF; serial procedure for multiplicity using Holm procedure within endpoint groups; ANCOVA model for primary endpoint with treatment and stratification factors; Cochran-Mantel-Haenszel tests for responder endpoints; stratification by MMD (≤17 vs >17) and prior preventive use (yes vs no); power 90% for 350 patients per group assuming treatment effect ≥1 day and SD ≤4 days; SAS version 9.2 or higher used for analyses

Inclusion Criteria

  • Adults 18-65 years of age (inclusive)
  • Diagnosis of migraine at or before 50 years of age
  • History of chronic migraine for ≥12 months before screening per ICHD-3 criteria
  • Completed headache eDiary on ≥24 of 28 days during screening period before randomization
  • Experienced ≥15 to ≤26 headache days during 28-day screening period
  • Experienced ≥8 migraine days during 28-day screening period
  • If using prescription or over-the-counter acute or preventive migraine medication: medications prescribed/recommended by healthcare professional
  • If using preventive migraine medication: stable for ≥3 months before screening
  • If using hormonal therapy (contraceptive, hormone replacement): stable and ongoing ≥3 months before screening
  • If using barbiturates or prescription opioids: ≤4 days/month, stable for ≥2 months before screening, maintained through week 24
  • Patients with CM and medication-overuse headache eligible except for overuse of barbiturates or opioids

Exclusion Criteria

  • Confounding pain disorder or clinically significant pain syndromes
  • Uncontrolled or untreated psychiatric conditions
  • Acute or active temporomandibular disorders
  • History or diagnosis of headache/migraine disorders not meeting ICHD-3 beta Section 1.3 criteria for CM
  • Present or previous malignancies (except squamous/basal cell carcinoma with excision for cure or breast/cervical cancer ≥10 years since diagnosis without recurrence)
  • Any active, progressive, or unstable cardiovascular, neurologic, or autoimmune disorder
  • Newly diagnosed or uncontrolled hypertension (mild primary hypertension well controlled for ≥6 months allowed)
  • History or evidence of substance abuse or dependence
  • Clinically significant abnormal ECG findings
  • Concurrent medical condition or laboratory abnormality during screening or before day 0 dosing
  • Body mass index ≥39 kg/m²
  • Recent or planned surgery requiring general anesthesia within 8 weeks before screening or during study
  • Experimental/unregistered therapy within 30 days or 5 plasma half-lives before screening
  • Prohibited devices, neuromodulation, neurostimulation, or injectable therapy within 2 months before screening or during screening
  • Botulinum toxin (any type) for migraine or cosmetic reasons within 4 months before screening or during screening
  • Monoamine oxidase inhibitors, ketamine, methylergonovine, or nimesulide within 3 months before screening or during screening
  • Any monoclonal antibody treatment within 6 months of screening
  • Prior eptinezumab or any monoclonal antibody targeting CGRP pathway
  • Women who were pregnant, breastfeeding, or planning pregnancy during study
  • Participating in any other clinical study
  • Positive for HIV, hepatitis B surface antigen, or hepatitis C

Baseline Characteristics

Eptinezumab 100 mg:

  • Sample size: 356
  • Age (years): 41.0 ± 11.7
  • Female (%): 86.2
  • White (%): 93.3
  • Hispanic or Latino (%): 9.3
  • Weight (kg): 73.3 ± 15.6
  • Height (cm): 166.2 ± 8.2
  • BMI (kg/m²): 26.4 ± 5.0
  • Age at migraine diagnosis (years): 22.8 ± 10.6
  • Duration of migraine diagnosis (years): 18.3 ± 12.2
  • Duration of CM (years): 11.6 ± 11.7
  • Headache days/month: 20.4 ± 3.1
  • Migraine days/month: 16.1 ± 4.6
  • Medication-overuse headache diagnosis (%): 39.0
  • Triptan use ≥33% of days (%): 34.8
  • Opioid or barbiturate use at any time (%): 12.9

Eptinezumab 300 mg:

  • Sample size: 350
  • Age (years): 41.0 ± 10.4
  • Female (%): 89.7
  • White (%): 92.0
  • Hispanic or Latino (%): 5.1
  • Weight (kg): 72.7 ± 15.3
  • Height (cm): 166.1 ± 7.9
  • BMI (kg/m²): 26.2 ± 5.0
  • Age at migraine diagnosis (years): 22.0 ± 9.3
  • Duration of migraine diagnosis (years): 19.0 ± 11.5
  • Duration of CM (years): 12.4 ± 11.2
  • Headache days/month: 20.4 ± 3.2
  • Migraine days/month: 16.1 ± 4.8
  • Medication-overuse headache diagnosis (%): 42.0
  • Triptan use ≥33% of days (%): 35.7
  • Opioid or barbiturate use at any time (%): 11.1

Placebo:

  • Sample size: 366
  • Age (years): 39.6 ± 11.3
  • Female (%): 88.8
  • White (%): 87.7
  • Hispanic or Latino (%): 9.6
  • Weight (kg): 74.8 ± 16.2
  • Height (cm): 166.3 ± 7.9
  • BMI (kg/m²): 27.0 ± 5.6
  • Age at migraine diagnosis (years): 22.6 ± 10.0
  • Duration of migraine diagnosis (years): 17.0 ± 11.6
  • Duration of CM (years): 11.6 ± 10.9
  • Headache days/month: 20.6 ± 2.99
  • Migraine days/month: 16.2 ± 4.6
  • Medication-overuse headache diagnosis (%): 39.6
  • Triptan use ≥33% of days (%): 31.7
  • Opioid or barbiturate use at any time (%): 13.1

Arms

FieldEptinezumab 100 mg + PlaceboEptinezumab 300 mg + PlaceboControl
InterventionEptinezumab 100 mg IV administered over 30 minutes (plus additional 15 minutes if required per protocol) on day 0 and week 12; reconstituted in total volume of 100 mL 0.9% saline; patients monitored for ≥2 hours after treatment; double-dummy design with matching topiramate placebo; dose escalation to 140 mg not permitted; 73.5% started with 70 mg, 26.5% started with 140 mg, 42.5% had dose increased during trialEptinezumab 300 mg IV administered over 30 minutes (plus additional 15 minutes if required per protocol) on day 0 and week 12; reconstituted in total volume of 100 mL 0.9% saline; patients monitored for ≥2 hours after treatment; double-dummy design with matching topiramate placebo; dose adjustments not permittedMatching placebo IV administered over 30 minutes (plus additional 15 minutes if required per protocol) on day 0 and week 12; reconstituted in total volume of 100 mL 0.9% saline; patients monitored for ≥2 hours after treatment; double-dummy design
Duration24 weeks (with dosing on day 0 and week 12)24 weeks (with dosing on day 0 and week 12)24 weeks (with dosing on day 0 and week 12)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change from baseline in mean monthly migraine days (MMDs) over weeks 1 to 12, assessed with electronic diary (eDiary) data; migraine day defined using ICHD-3 criteria (lasted ≥4 hours or 30 min-4 hours relieved by acute medication; ≥2 pain features: unilateral, pulsating, moderate/severe intensity, aggravation by physical activity; ≥1 associated symptom: nausea/vomiting or photophobia and phonophobia)PrimaryMean -5.6 days (from 16.2 to 10.5 days)100 mg: Mean -7.7 days (from 16.1 to 8.5 days); 300 mg: Mean -8.2 days (from 16.1 to 7.9 days)100 mg: <0.0001; 300 mg: <0.0001
≥75% migraine responder rate over weeks 1-4Secondary57/366 (15.6%)100 mg: 110/356 (30.9%); 300 mg: 129/350 (36.9%)100 mg: OR 2.4 (95% CI 1.7-3.5), difference 15.3% (9.3-21.4); 300 mg: OR 3.2 (95% CI 2.2-4.6), difference 21.3% (15.0-27.6)<0.0001 for both doses
≥75% migraine responder rate over weeks 1-12Secondary55/366 (15.0%)100 mg: 95/356 (26.7%); 300 mg: 116/350 (33.1%)100 mg: OR 2.0 (95% CI 1.4-3.0), difference 11.7% (5.8-17.5); 300 mg: OR 2.8 (95% CI 1.9-4.0), difference 18.1% (12.0-24.3)100 mg: 0.0001; 300 mg: <0.0001
≥50% migraine responder rate over weeks 1-12Secondary144/366 (39.3%)100 mg: 205/356 (57.6%); 300 mg: 215/350 (61.4%)100 mg: OR 2.1 (95% CI 1.6-2.8), difference 18.2% (11.1-25.4); 300 mg: OR 2.4 (95% CI 1.8-3.3), difference 22.1% (14.9-29.2)<0.0001 for both doses
Percentage of patients with migraine on day 1 after dosingSecondary42.3%100 mg: 28.6%; 300 mg: 27.8%<0.0001 for both doses vs placebo
Change from baseline in average daily percentage of patients with migraine over weeks 1-4SecondaryMean -18.8% (from 58% baseline)100 mg: Mean -27.1%; 300 mg: Mean -29.8%100 mg: difference -8.3% (-11.5 to -5.0); 300 mg: difference -11.0% (-14.2 to -7.8)<0.0001 for both doses
Change in HIT-6 total score from baseline to week 12SecondaryMean -4.5 (from 64.8 to 60.5)100 mg: Mean -6.2 (from 65.0 to 58.8); 300 mg: Mean -7.3 (from 65.1 to 57.6)100 mg: difference -1.7 (-2.8 to -0.7); 300 mg: difference -2.9 (-3.9 to -1.8)100 mg: 0.0010 (nominally significant); 300 mg: <0.0001
Change in acute migraine medication use days from baseline to weeks 1-12SecondaryMean -1.9 days (from 4.3 days)100 mg: Mean -3.3 days (from baseline); 300 mg: Mean -3.5 days (from baseline)100 mg: difference -1.2 (-1.7 to -0.6); 300 mg: difference -1.4 (-1.9 to -0.9)100 mg: <0.0001 (not formally tested); 300 mg: <0.0001
Change in mean headache days over weeks 1-12SecondaryMean -6.4 days (from 20.6 to 14.1 days)100 mg: Mean -8.2 days (from 20.4 to 12.2 days); 300 mg: Mean -8.8 days (from 20.4 to 11.7 days)100 mg: difference -1.7 (-2.6 to -0.9); 300 mg: difference -2.3 (-3.2 to -1.4)Not specified for this exploratory endpoint
HIT-6 scores in severe range at week 12Secondary60.1% at week 12 (from 87.4% at baseline)100 mg: 51.4% at week 12 (from 89.6% at baseline); 300 mg: 42.9% at week 12 (from 88.6% at baseline)
Any treatment-emergent AEAdverse171/366 (46.7%)100 mg: 155/356 (43.5%); 300 mg: 182/350 (52.0%)
Study drug-related TEAEsAdverse29/366 (7.9%)100 mg: data included in 93/706 (13.2%) for combined eptinezumab groups
NasopharyngitisAdverse22/366 (6.0%)100 mg: 19/356 (5.3%); 300 mg: 33/350 (9.4%)Only TEAE reported >2% in eptinezumab-treated patients at incidence >2% over placebo
Upper respiratory tract infectionAdverse20/366 (5.5%)100 mg: 15/356 (4.2%); 300 mg: 19/350 (5.4%)
SinusitisAdverse15/366 (4.1%)100 mg: 7/356 (2.0%); 300 mg: 9/350 (2.6%)
MigraineAdverse16/366 (4.4%)100 mg: 6/356 (1.7%); 300 mg: 8/350 (2.3%)
Urinary tract infectionAdverse6/366 (1.6%)100 mg: 8/356 (2.2%); 300 mg: 12/350 (3.4%)
NauseaAdverse7/366 (1.9%)100 mg: 6/356 (1.7%); 300 mg: 12/350 (3.4%)Study drug-related: 100 mg + 300 mg: 11 (1.6%), placebo: 1 (<1%)
FatigueAdverse7/366 (1.9%)100 mg: 8/356 (2.2%); 300 mg: 6/350 (1.7%)Study drug-related: 100 mg + 300 mg: 13 (1.8%), placebo: 3 (<1%)
Serious adverse eventsAdverse3/366 (<1%)100 mg + 300 mg: 7/706 (<1%)Most frequent: nervous system disorders, injury/poisoning/procedural complications, psychiatric disorders
Study drug-related serious AEAdverse01 patient (300 mg): worsening migrainous visual phenomena, 126 days after second dose, lasted 4 days
Life-threatening serious AEsAdverse00
DeathsAdverse00
TEAEs leading to study drug withdrawalAdverse2/366 (<1%)100 mg: 3/356 (<1%); 300 mg: 8/350 (2.3%)Total: 13/1072 (1.2%)
Hypersensitivity leading to withdrawalAdverse0300 mg: 6/350 (1.7%); all mild-moderate, treatment-day events, resolved same day or within 2 days3 after first dose, 3 after second dose
Seizure (SAE)Adverse01 patient (300 mg): required hospitalization, assessed as not study drug-related, resolved same day
AEs of special interestAdverseOccurred in <1% of total groupOccurred in <1% of total groupIncluded: Columbia-Suicide Severity Rating Scale-associated AEs, cardiovascular AEs, hepatic AEs, hypersensitivity and anaphylaxis AEs
Anti-drug antibodies (ADAs) at week 24AdverseNot applicable100 mg: 56/326 (17.2%); 300 mg: 56/329 (17.0%); declined by week 32No clear dose-response trend; did not affect efficacy or safety
ADAs with neutralizing potential (NAbs)AdverseNot applicable100 mg: 26 patients; 300 mg: 19 patients; 24/112 (21.4%) of ADA-positive patients at week 24 were NAb-positiveNo impact on efficacy or safety

Subgroup Analysis

Post hoc analysis in patients with no barbiturate or opioid use at any time showed similar MMD reduction compared to placebo (100 mg -2.3 [-3.2 to -1.4], p<0.0001; 300 mg -2.8 [-3.7 to -1.9], p<0.0001)

Criticisms

  • Open-label with respect to route of administration (IV therapy), though double-blind regarding drug vs placebo and dose
  • High placebo response rate (5.6-day reduction) attributed to novelty of treatment, IV administration, multiple active treatment arms increasing expectations, high percentage of preventive-naïve patients (59.4%), and intensive patient contact with migraine experts
  • Excluded patients with significant cardiovascular disease or clinically significant concurrent medical conditions, limiting generalizability to these populations
  • Excluded patients with >26 headache days during screening period, limiting applicability to most severe CM patients
  • Excluded patients with history of significant opioid (≥5 d/mo) or barbiturate use, limiting applicability to regions with high opioid prescribing patterns
  • Single ethnicity dominance: 91.0% White, 8.0% Hispanic/Latino, limiting generalizability to other ethnic groups
  • Industry-sponsored trial (H. Lundbeck A/S) with multiple authors as employees or with financial relationships
  • Relatively short follow-up for primary endpoint (12 weeks) though study continued to 32 weeks
  • No direct comparison to other approved preventive treatments for CM (e.g., onabotulinumtoxinA, other CGRP mAbs)
  • 40.2% of patients had medication-overuse headache at baseline; results may differ in non-MOH CM population
  • Protocol amendment during trial to include chronic migraine patients after 43.8% had been enrolled as episodic migraine only
  • Serial testing procedure controlled for multiplicity but some secondary endpoints (e.g., 100 mg HIT-6) nominally significant but not formally tested
  • Formation of ADAs observed (peak 17% at week 24) though no impact on efficacy or safety demonstrated; long-term immunogenicity unknown
  • IV administration requires healthcare setting and monitoring, less convenient than subcutaneous or oral preventives

Funding

H. Lundbeck A/S (Copenhagen, Denmark)

Based on: PROMISE-2 (Neurology, 2020)

Authors: Richard B. Lipton, Peter J. Goadsby, Jeff Smith, ..., Roger Cady

Citation: Neurology. 2020;94:e1365-e1377. doi:10.1212/WNL.0000000000009169

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