. 2022 May 31;15:17562864221095902. doi: 10.1177/17562864221095902

Table 2.

Studies of migraine preventive therapies reporting an early onset of preventive effect^*: clinical efficacy endpoints.

Study	Study design	Population	Dose	Early onset timepoint	Onset of preventive effect	GRADE Ranking^†
Erenumab
NCT02456740 (STRIVE) and NCT02066415²¹	Post hoc analysis of two R, DB, PC studies (NCT02456740: Phase II; NCT02066415: Phase III)	Adults with EM (N = 955) and CM (N = 667)	70 or 140 mg monthly	EM Week 1	Nominally significant reductions in WMD versus placebo as early as Week 1 (not adjusted for multiple comparisons) LSM change from baseline (95%CI) Week 1 Placebo: −0.1 (−0.3, 0.0) Erenumab 70 mg: −0.3 (−0.5, −0.2); p = 0.130 Erenumab 140 mg: −0.6 (−0.7, −0.4); p < 0.001 Week 4 Placebo: −0.4 (−0.5, −0.2) Erenumab 70 mg: −0.6 (−0.8, −0.5); p = 0.029 Erenumab 140 mg −0.6 (−0.8, −0.5); p = 0.019	High
				CM Week 1	Nominally significant reductions in WMD versus placebo for both doses at Week 1 and sustained through Week 4 Week 1 Placebo: −0.5 (−0.8, −0.3) Erenumab 70 mg: −0.9 (−1.2, −0.7); p = 0.047 Erenumab 140 mg: −0.8 (−1.1,−0.5); p = 0.18 Week 4 Placebo: −0.8 (−1.0, −0.6) Erenumab 70 mg: −1.5 (−1.7, −1.2); p < 0.001 Erenumab 140 mg: −1.4 (−1.6, −1.1); p = 0.002
NCT02483585 (ARISE)²²	Phase III, R, DB, PC	577 adults (18–65 years) with EM	70 mg monthly	Month 1	Primary outcome: LSM change from baseline in MMD at Month 3, −2.9 days versus −1.8 days (p < 0.001) Exploratory: Reduction in MMD achieved nominal significance (not adjusted for multiple comparisons) at Month 1 (p < 0.001 versus placebo)	Moderate
Fremanezumab
NCT02629861 (HALO EM)^23,24	Phase III, R, DB, PC	875 adults (18–70 years) with EM	Monthly (225 mg) Quarterly (675 mg at Month 1, placebo at Months 2 and 3), placebo	Day 1	Both regimens reduced mean weekly headache days at Week 1 versus placebo (monthly, −0.9 versus −0.3; quarterly, −0.8 versus −0.3; both p < 0.0001) (mixed-effect model for repeated measures) More patients reported no migraine by the next day following the first injection [monthly, 79.4%; quarterly, 79.2% versus placebo, 66.6% (p = 0.0002 and 0.0004 versus placebo, respectively)] (post hoc analysis)	High
NCT02621931 (HALO CM)^25,26	Phase III, R, DB, PC	1130 adults (18–70 years) with CM	Monthly (675 mg followed by 225 mg at Months 2 and 3) or quarterly (675 mg at Month 1, followed by placebo injections at Months 2 and 3)	Day 1	Reduced mean weekly headache days at Week 1 versus placebo (−1.1 versus −0.5; p < 0.0001) (mixed-effect model for repeated measures) More patients reported no headache of at least moderate severity by the next day following the first injection (fremanezumab, 69%; placebo, 61%; p = 0.0036) (post hoc analysis)	High
NCT02025556 (HFEM)²⁷	Post hoc analysis of a 16-week, phase II, R, DB, PC study	297 adults (18–65 years) with high-frequency EM	225 or 675 mg monthly	Week 1	Significantly reduced migraine frequency compared to placebo within the first week of therapy; LSM differences versus placebo at Week 1 were −0.93 WMD and −1.02 WMD, both p < 0.0001 The benefit was maintained for the second and third weeks of therapy (p < 0.001); weekly mean headache days and headache hours were also reduced (p < 0.01)	Moderate
NCT02021773²⁸	Phase IIb, R, DB, PC (post hoc analysis)	261 adults (18–65 years) with CM	900 mg (225 mg monthly × 4) or 675/225 (675 Month 1 then 225/month × 3)	Days 3–7	900 mg: reduced mean headache hours from baseline to Day 3 (−3.08 versus +0.36 for placebo, p = 0.0331) 675/225: reduced mean headache hours from baseline to Day 7 (−7.28 versus −1.59, p = 0.0486)	Moderate
Galcanezumab
NCT01625988(ART-01)²⁹	Post hoc analysis of a Phase II, R, DB, PC study	217 adults (18–65 years) with EM	150 mg every 2 weeks	Week 1	Reduced weekly mean headache days from baseline at Week 1 (−0.89) versus placebo (−0.53; p = 0.018) Greater proportion of patients experienced ⩾ 50% reduction in number of weekly mean headache days at Week 1 (62% versus 42%; p < 0.05)	Moderate
NCT02614183 (EVOLVE-1) and NCT02614196 (EVOLVE-2)³⁰	Post hoc analysis of two Phase III, R, DB, PC studies	1773 adults (18–65 years) with EM	120 mg monthly with loading dose of 240 mg administered the first month	Day 1	Reduced mean headache days at Week 1 (OR 2.71 and 2.88 for EVOLVE-1 and EVOLVE-2 respectively; both p < 0.001) (repeated measures ordinal logistic regression) The mean number of patients with migraine headaches each day of Week 1 was significantly lower with galcanezumab versus placebo beginning Day 1 post-injection (EVOLVE-1, p = 0.002; EVOLVE-2, p = 0.038)	High
Eptinezumab
NCT01772524³¹	Phase II, R, DB, PC	174 adults (18–55 years) with EM	1000 mg, placebo	Month 1	Reduced mean MMD between baseline and Week 1–4 versus placebo (−5.6 versus −3.9, p = 0.0007)	Moderate
NCT02275177³²	Phase IIb, R, DB, PC (post hoc analysis)	616 adults (18–55 years) with CM	10, 30, 100, 300 mg, placebo	Day 1	Eptinezumab 100 and 300 mg reduced the likelihood of a migraine attack more than placebo in the 24 h post-infusion versus baseline Migraine attack on Day 1: Eptinezumab 100 mg, 29.3%; eptinezumab 300 mg, 26.3%; placebo, 48.7% versus migraine occurrence on any given day during 28-day screening period: Eptinezumab 100 mg, 60.4%; eptinezumab 300 mg, 59.1%; placebo, 58.7%	Moderate
NCT02559895 (PROMISE-1)³³	Phase III, R, DB, PC	888 adults (18–75 years) with EM	30, 100, 300, placebo	Day 1	Eptinezumab 100 and 300 mg reduced the likelihood of a migraine attack in the 24 h post-infusion 50% versus baseline and significantly more than placebo Overall baseline prevalence, 30.7% Day 1 prevalence: Eptinezumab 100 mg, 14.8%; eptinezumab 300 mg, 13.9%; placebo, 22.5% (p = 0.0312 and p = 0.0159 versus placebo, respectively)	High
NCT02974153 (PROMISE-2)³⁴	Phase III, R, DB, PC	1072 adults (18–65 years) with CM	100, 300 mg, placebo	Day 1	Eptinezumab 100 and 300 mg reduced the likelihood of a migraine attack in the 24 h post-infusion 50% versus baseline and significantly more than placebo Overall baseline prevalence, 58%; Day 1 prevalence: Eptinezumab 100 mg, 28.6%; eptinezumab 300 mg, 27.8%; placebo, 42.3% (both p < 0.001 versus placebo)	High
OnabotulinumtoxinA
NCT00156910 (PREEMPT 1) and NCT00168428 (PREEMPT 2)¹²	Phase III, R, DB, PC	1384 adults (18–65 years) with CM	155–195 U every 12 weeks	Week 1	Reduced headache and migraine days versus placebo compared to Week 4 of baseline (−0.9 versus −0.7 headache days/week, p = 0.046; −1.0 versus −0.7 migraine days/week, p = 0.031)	Moderate
				Week 3	Reduced headache and migraine days versus placebo compared to Week 4 of baseline (−1.6 versus −1.1 headache days/week, p < 0.001; −1.6 versus 1.1 migraine days/week, p < 0.001)

CI, confidence interval; CM, chronic migraine; DB, double-blind; EM, episodic migraine; LSM, least-squares mean; MMD, monthly migraine days; OR, odds ratio; PC, placebo-controlled; R, randomized; WMD, weekly migraine days.

Early was defined as the demonstration of preventive benefits within 1 month (30 days) post-initiation.

^†

Grading criteria based on the GRADE methodology of assessing the certainty in evidence and the strength of recommendations.¹⁹