OnabotulinumtoxinA for the prophylactic treatment of headaches in adult patients with chronic migraine: a safety evaluation

Figures & data

Table 1. OnabotulinumtoxinA efficacy in key clinical and real-world studies

Study name	Study design and duration	Number of patients	Patient characteristics	Key efficacy outcomes
PREEMPT 1, Aurora et al [2010, 47]	DB, placebo-controlled, randomized trial with OL phase DB phase: 24 weeks	OnabotA: 341 Placebo: 338	CM, age 18–65, 59–64% used ≥1 preventative, 66–70% medication overuse	At 24 weeks (DB phase): No difference in headache episodes (onaBoNTA −5.2, placebo −5.3, p = 0.34) Reduced headache days/28 days (−1.4 vs placebo, p = 0.006), migraine days/28 days (−1.5vs placebo, p = 0.002), number of moderate/severe days/28 days (−1.4 vs placebo, p = 0.004), HIT6 (−2.3 vs placebo, p < 0.001), % patients with HIT6 ≥ 60 (−11%, p = 0.001)
PREEMPT 2, Diener et al [2010, 48]	DB, placebo-controlled, randomized trial with OL phase DB phase: 24 weeks	OnabotA: 347 Placebo: 358	CM, age 18–65, 64–66% used ≥1 preventative, 62–63% medication overuse	At 24 weeks (DB phase): Reduced headache days/28 days (−2.3 vs placebo, p < 0.001), migraine days/28 days (−2.4 vs placebo, p < 0.001), moderate/severe headache days/28 days (−2.5 vs placebo, p < 0.001), headache episode frequency (−0.7, p = 0.003), HIT6 score (−2.5 vs placebo, p < 0.001), % patients with HIT6 ≥ 60 (−10.2% vs placebo, p = 0.003)
Dodick et al [2010, 49]	PREEMPT 1 and 2 pooled DB phase 24 weeks	OnabotA: 688 Placebo: 696	CM, age 18–65, 64–66% medication overuse	At 24 weeks (DB phase): Reduced headache days/28 days (−1.8 vs placebo, p < 0.001), migraine days/28 days (−2.0 vs placebo, p < 0.001), moderate/severe headache days/28 days (−1.9 vs placebo, p < 0.001), headache episode frequency (−0.3, p = 0.009), HIT6 score (−2.4 vs placebo, p < 0.001), % patients with HIT6 ≥ 60 (−10.6% vs placebo, p < 0.001)
Aurora et al [2011, 50]	PREEMPT 1 and 2 pooled DB + OL phase 56 weeks	OnabotA: 688 Placebo: 696	CM, age 18–65, 64–66% medication overuse	At 56 weeks (DB+OL phases): Headache day frequency/28 days vs baseline: O/O − 12.17, P/O − 11.32. Reduced headache days/28 days (−0.9 vs P/O, p = 0.019), migraine days/28 days (−0.9 vs P/O, p = 0.018), moderate/severe headache days/28 days (−0.8 vs P/O, p = 0.027), total headache hours on headache days (−23.4 vs P/O, p = 0.018)
Aurora et al [2014, 51]	PREEMPT 1 and 2 pooled DB + OL phase 56 weeks	Patients completing all 5 treatment cycles: 1005 O/O: 515, P/O: 492	CM, age 18–65,	At 56 weeks (DB+OL phase): Reduced headache days/28 days (−0.9 vs P/O, p = 0.035), migraine days/28 days (−0.9 vs P/O, p = 0.038), moderate/severe headache days/28 days (−0.9 vs P/O, p = 0.042), HIT6 score (−0.6 vs P/O, p = 0.157)
COMPEL, Blumenfeld et al [2018, 55]	OL prospective study, 35 centers, USA, Australia, South Korea 108 weeks	716	CM, age ≥18, ≤1 oral preventative	At 108 weeks (vs baseline): Reduced headache days/28 days (−10.7, p < 0.0001), moderate/severe headache days/28 days (−9.5, p < 0.0001), HIT6 score (−7.1, p < 0.0001). 61.1% patients had ≥50% headache day reduction Reduced headache days/28 days at week 24, 60, 84 and 108 vs baseline (p < 0.0001)
REPOSE, Ahmed et al [2019, 60]	Real-world OL study, 78 centers, Europe 2 years	633 (Mean 5.5 cycles, range 1–13)	CM, 41% with medication-overuse	At 2 years (vs baseline): Reduced MHD at all timepoints (20.6 to 7.4, p < 0.01), improved MSQ scores (restrictive: 17.3 to 33.6, preventive: 15.3 to 28.9, emotional: 17.9 to 34.9, p < 0.001), EQ-5D total score (0.69 to 0.89, p < 0.001) and health state score (50 to 70, p < 0.001)
Khalil et al [2014, 61]	Real-world OL study, single-center, UK ≥1 cycle	254 (455 cycles)	CM, all used ≥1 preventative (94% used ≥3 preventatives), 50% medication-overuse	Vs baseline: improved MHD (−7, p < 0.001), MMD (−6, p < 0.001), crystal clear days (+7, p < 0.001), days requiring triptans (−3. p < 0.001), days requiring painkillers (−3, p < 0.001), HIT6 (−9.7, p < 0.001). Hull criteria (≥50% reduction in MHD, (≥50% reduction in MHD, or doubling of HFD if ≥3 HFD at baseline or HFD >6 if <3 HFD at baseline): 34% met 0/3 criteria 24% met 1/3 criteria 16% met 2/3 criteria 26% met 3/3 criteria
Ahmed et al [2021, 62]	Real-world OL study, single-center, UK ≥2 years	655	CM, 100% used ≥1 preventative (98% used ≥3 preventatives), 53% medication-overuse	Vs baseline: improved MHD (−8, p < 0.001), MMD (−6, p < 0.001), crystal clear days (+7, p < 0.001), HIT6 (−6, p < 0.001). After Cycle 2: 58% (380) responders by Hull criteria (48% by NICE criteria) At 2 years (380 responders): 152 continued treatment, 28 became resistant on treatment, 61 converted to EM then reverted to CM and restarted treatment, 112 converted to EM and stopped treatment
Andreou et al [2018, 63]	Real-world OL study, single-center, UK	200	CM, 100% used ≥3 preventatives, 46% with medication-overuse	After 2 cycles (vs baseline): Reduced MHD (24.0 to 11.3, p < 0.025), MMD (13.0 to 5.0, p < 0.025), crystal clear headache-free day (0 to 12.8, p < 0.025), HIT6 score (70 to 64, p < 0.025) After Cycle 2: 64% responder (≥30% MHD reduction after 2 cycles). In responders, MHD (baseline 23) reduced to 8, 8, 8, 11 after cycles 2, 5, 8, 13. 34% converted to EM (29.4% after 2 cycles)
Negro et al [2015, 64]	Real-world OL study, single-center, Italy 2 years	155	CM, 100% used ≥1 preventative, 100% with MOH	After 2 years (vs baseline): Reduced MHD (22.3 to 7.3, p < 0.001), MMD (21.4 to 6.8, p < 0.001), acute medication days (20.8 to 5.3, p < 0.001), HIT6 score (68.9 to 52.0, p < 0.001)
Negro et al [2015, 65]	Real-world OL study, single-center, Italy 2 years	172 (195 units onabotA per patient)	CM, 100% used ≥1 preventative, 100% with MOH	After 2 years (vs baseline): Reduced MHD (22.2 to 4.1, p ≤ 0.05), MMD (21.6 to 3.8, p ≤ 0.05), acute medication days (21.0 to 3.7, p ≤ 0.05), HIT6 score (67.9 to 49.0, p ≤ 0.05)
Dominguez et al [2018, 66]	Real-world OL study, 13 centers, Spain 1 year	725	CM, 100% used ≥2 preventatives including topiramate, 58% with MOH	After 1 year (vs baseline): Reduced MHD (21.8 to 8.4, p < 0.01), MMD (13.8 to 6.0, p < 0.01), analgesic days (17.0 to 6.3, p < 0.01), MIDAS score (35.9 to 9.1, p < 0.01)
Ahmed et al [2019, 67]	Real-world OL study, single-center, UK. 8 years	851	CM, 100% used ≥1 preventative (98% used ≥3 preventatives), 53% medication-overuse	52.6% responders by Hull criteria

CM chronic migraine, DB double-blind, EM episodic migraine, EQ-5D EuroQoL 5 Dimension Questionnaire, HIT6 score Headache Impact Test-6 score, MHD monthly headache days, MIDAS The migraine disability assessment test, MOH medication-overuse headache, MSQ Migraine specific quality of life questionnaire, OL open-label, OO onabotA/onabotA group, PO placebo/onabotA group.

Table 2. OnabotulinumtoxinA adverse events and tolerability in key clinical and real-world studies

	PREEMPT 1, Aurora et al [2010, 47]	PREEMPT 2, Diener et al (2010 48)	Dodick et al (2010 49)	Aurora et al (2011 50)	Aurora et al (2014 51)	Diener et al [2014, 69]	COMPEL, Winner et al [2019, 71]	Khalil et al (2014 61)	Andreou et al [2019, 63]	Dominguez et al [2018, 66]	Negro et al (2015 64)	REPOSE, Ahmed et al [2019, 60]	CM-PASS, Matharu et al [2017, 70]	Ahmed et al [2019, 67]	Total numbers of unique study patients
Study design	DB, placebo-controlled, randomized trial with OL phase	DB, placebo-controlled, randomized trial with OL phase	PREEMPT 1 and 2 pooled 24 week DB phase	PREEMPT 1 and 2 pooled DB plus 32 week OL phase	PREEMPT 1 and 2- all Pt treated with 3–5 cycles	4-trial pooled data: PREEMPT 1 and 2 plus 2 Phase II trials	OL prospective study, 35 centers, USA, Australia, South Korea	Real- world OL study, single-center, UK	Real-world OL study, single-center, UK	Real-world OL study, 13 centers, Spain	Real- world single-center OL study, Italy, CM + MOH	Real- world OL study, 78 centers, Europe	Real- world multi-center OL study, Europe	Real- world OL study, single-center, UK
Study duration	DB phase- 24 weeks	DB phase- 24 weeks	DB phase- 24 weeks	OL phase- 32 weeks	56 weeks	≥ 1 cycle (16,926 patient-months)	108 weeks	≥ 1 cycle	6 –36 months	1 year	2 years	2 years	64 weeks	8 years
Number of onabotA-treated patients (N)	340	347	687	1205 at start of OL phase	1005	1997	716	254	200	725	155	633	1160	972	6558
Any AEs, n (%)	203 (59.7%)	226 (65.1%)	429 (62.4%)	703 (58.3%)	775 (77.1%)	1455 (72.9%)	436 (60.9%)	n/a	n/a	89 (12.3%) after 1 cycle, 37 (5.1%) after 12 months	n/a	n/a	478 (41.2%)	88 (12.6%)	2546
TRAEs	86 (25.3%)	116 (33.4%)	202 (29.4%)	245 (20.3%)	332 (33.0%)	n/a	131 (18.3%)	n/a	n/a	n/a	23 (17.5%)^c	116 (18.3%)	291 (25.1%)	n/a	893
Serious AEs	18 (5.3%)	15 (4.3%)	33 (4.8%)	46 (3.8%)	62 (6.2%)	107 (5.4%)	75 (10.5%)	n/a	0 (0%)	n/a	0 (0%)	n/a	61 (5.3%)	n/a	243
Serious TRAEs	0 (0%)	1 (0.3%)	1 (0.1%)	1 (0.1%)	1 (0.1%)	n/a	1 (0.1%)	n/a	n/a	n/a	0 (0%)	8 (1.3%)	1 (<0.1%)	n/a	11
Mild, n (%)	Majority	Majority	Majority	Majority	n/a	318 (15.9%)^a	n/a	n/a	n/a	76 (10.2%)	All	45 (7.1%)	n/a	n/a	439
Moderate, n (%)					n/a	711 (35.6%)	n/a	n/a	n/a	n/a		47 (7.4%)	n/a	n/a	758
Severe, n (%)	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	0 (0%)	n/a	0 (0%)	24 (3.8%)	n/a	n/a	24
Neck pain	20 (5.9%)	26 (7.5%)	46 (8.7%)	55 (4.6%)	22 (4.3%)^b	252 (12.6%)	29 (4.1%)	n/a	2 (1.0%)	n/a	5 (3.8%)^c	18 (2.8%)	51 (4.4%)	n/a	357
Muscle weakness	20 (5.9%)	18 (5.2%)	38 (5.5%)	47 (3.9%)	8 (1.6%)^b	160 (8.0%)	10 (1.4%)	n/a	2 (1.0%)	n/a	5 (3.8%)^c	N/A	31 (2.7%)	n/a	208
Eyelid ptosis	n/a	<5%	23 (3.3%)	30 (2.5%)	10 (1.9%)^b	91 (4.6%)	18 (2.5%)	28 (11.0%)	14 (7.0%)	n/a	4 (2.9%)^c	34 (5.4%)	47 (4.1%)	58 (6.8%)	294
Injection-site pain	n/a	n/a	22 (3.2%)	24 (2.0%)	11 (2.1%)^b	89 (4.5%)	14 (2.0%)	38 (14.9%)	n/a	n/a	4 (3.3)^c	n/a	n/a	n/a	145
Headache	n/a	n/a	20 (2.9%)	17 (1.4%)	n/a	142 (7.1%)	12 (1.7%)	n/a	n/a	n/a	5 (3.7%)^c	n/a	n/a	n/a	159
Migraine	n/a	n/a	n/a	n/a	n/a	88 (4.4%)	7 (1.0%)	11 (4.3%)	n/a	n/a	n/a	n/a	34 (2.9%)	n/a	140
Myalgia	n/a	<5%	18 (2.6%)	15 (1.2%)	n/a	58 (2.9%)	n/a	n/a	n/a	n/a	n/a	n/a	11 (0.9%)	n/a	69
Muscle stiffness	n/a	<5%	16 (2.3%)	20 (1.7%)	n/a	122 (6.1%)	17 (2.4%)	37 (14.6%)	n/a	n/a	n/a	17 (2.7%)	23 (2.0%)	Present	216
Musculoskeletal pain	n/a	n/a	15 (2.2%)	13 (1.1%)	n/a	89 (4.5%)	n/a	n/a	n/a	n/a	n/a	n/a	10 (0.9%)	n/a	99
Facial paresis	n/a	n/a	n/a	n/a	n/a	122 (6.1%)	9 (1.3%)	15 (5.9%)	n/a	n/a	n/a	n/a	15 (1.3%)	n/a	160
Facial spasm	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	11 (0.9%)	n/a	11
Dysphagia	n/a	n/a	n/a	n/a	n/a	n/a	n/a	5 (1.96%)	1 (0.5%)	n/a	n/a	n/a	3 (0.3%)	n/a	9
Hypersensitivity	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	1 (0.5%)	n/a	n/a	n/a	10 (0.9%)	n/a	11
Fainting during injection	n/a	n/a	n/a	n/a	n/a	n/a	n/a	3 (1.2%)	1 (0.5%)	n/a	n/a	n/a	n/a	n/a	4
Skin tightness	n/a	n/a	n/a	n/a	n/a	n/a	7 (1.0%)	n/a	n/a	n/a	n/a	n/a	n/a	n/a	7
Discontinuation due to AEs, n (%)	14 (4.1%)	12 (3.5%)	26 (3.8%)	31 (2.6%)	n/a	67 (3.4%)	32 (4.5%), due to serious AE- 13 (1.8%)	n/a	0 (0%)	n/a	n/a	10 (1.6%)	51 (4.4%)	n/a	160
Deaths, n (%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	n/a	0 (0%)	n/a	n/a	0 (0%)	2 (0.2%)- not TRAE	n/a	2 (not TRAE)
Pregnancy outcomes	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	1 spontaneous abortion- unclear if treatment-related	n/a	n/a	1

AE adverse events, CM chronic migraine, DB double-blind phase, MOH medication-overuse headache, OL open label, TRAE treatment-related adverse events.

^aas proportion of all AEs

^bof 515 patients completing all 5 cycles

^cof 132 patients who completed study

Box 1. Drug summary

Drug name	OnabotulinumtoxinA, Botox
Phase	Post-authorization
Indications	UK: Chronic migraine prophylaxis in patients unresponsive to ≥3 previous pharmacological prophylactics with appropriately managed medication-overuse Europe: Symptom relief in adults fulfilling criteria for chronic migraine (headaches on ≥15 days per month, of which at least 8 days with migraine) in patients who have responded inadequately or are intolerant of prophylactic migraine medications US: Prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer)
Pharmacology description/mechanism of action	Direct inhibition of peripheral sensitisation and indirect inhibition of central sensitisation of the trigeminovascular system, by intraneuronal cleavage of presynaptic synaptosomal-associated fusion attachment protein of 25 kDa (SNAP25), leading to reduced proinflammatory neurotransmitter and neuropeptide release and nociceptive ion channel downregulation
Route of administration	Licensed administration regimen: 155–195 units via 31–39 intramuscular injections into head/neck muscle groups for all countries (excluding USA) PREEMPT paradigm: 12-weekly intramuscular administration into 7 head/neck muscle groups (155 total units in 31 sites)
Chemical structure	Purified neurotoxin complex (protein) derived from Clostridium botulinum
Pivotal studies	PREEMPT 1, PREEMPT 2, COMPEL, REPOSE

Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):793–803.

 PubMed Web of Science ®Google Scholar

Diener H-C, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):804–814.

 PubMed Web of Science ®Google Scholar

Dodick DW, Turkel CC, DeGryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50(6):921–936.

 PubMed Web of Science ®Google Scholar

Aurora SK, Winner P, Freeman MC, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled analysis of the 56-week PREEMPT clinical program. Headache. 2011;51(9):1358–1373.

 PubMed Web of Science ®Google Scholar

Aurora SK, Dodick DW, Diener H-C, et al. OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program. Acta Neurol Scand. 2014;129(1):61–70.

 PubMed Web of Science ®Google Scholar

Blumenfeld AM, Stark RJ, Freeman MC, et al. Long-term study of the efficacy and safety of onabotulinumtoxinA for the prevention of chronic migraine: COMPEL study. J Headache Pain. 2018;19(1):13.

 PubMedGoogle Scholar

Ahmed F, Gaul C, Garcia-Monco JC, et al. An open-label prospective study of the real-life use of onabotulinumtoxinA for the treatment of chronic migraine: the REPOSE study. J Headache Pain. 2019;20(1):26.

 PubMedGoogle Scholar

Khalil M, Zafar HW, Quarshie V, et al. Prospective analysis of the use of OnabotulinumtoxinA (BOTOX) in the treatment of chronic migraine; real-life data in 254 patients from Hull, UK. J Headache Pain. 2014;15(1):54.

 PubMedGoogle Scholar

Ahmed F, Buture A, Tanvir T, et al. Long term outcome for onabotulinumtoxinA (Botox) therapy in chronic migraine: a 2-year prospective follow-up audit of patients attending the Hull (UK) migraine clinic. Cephalalgia Rep. 2021;4:1–9.

 Google Scholar

Andreou AP, Trimboli M, Al-Kaisy A, et al. Prospective real-world analysis of onabotulinumtoxinA in chronic migraine post-national institute for health and care excellence UK technology appraisal. Eur J Neurol. 2018;25(8):1069–e83.

 PubMed Web of Science ®Google Scholar

Negro A, Curto M, Lionetto L, et al. OnabotulinumtoxinA 155 U in medication overuse headache: a two years prospective study. SpringerPlus. 2015;4(1):826.

 PubMedGoogle Scholar

Negro A, Curto M, Lionetto L, et al. A two years open-label prospective study of onabotulinumtoxinA 195 U in medication overuse headache: a real-world experience. J Headache Pain. 2015;17(1):1.

 PubMedGoogle Scholar

Dominguez C, Pozo-Rosich P, Torres-Ferrus M, et al. OnabotulinumtoxinA in chronic migraine: predictors of response. A prospective multicentre descriptive study. Eur J Neurol. 2018;25(2):411–416.

 PubMed Web of Science ®Google Scholar

Ahmed F, Buture A, Tanvir T, et al. Hull Prospective Analysis of OnabotulinumtoxinA (Botox) in the treatment of Chronic Migraine; a real-life data in 972 patients; updated results on over 8 years of experience [abstract no. IHC-PO-423]. Cephalalgia. 2019;39(1 Suppl):276–277.

 Google Scholar

Diener H-C, Dodick DW, Turkel CC, et al. Pooled analysis of the safety and tolerability of onabotulinumtoxinA in the treatment of chronic migraine. Eur J Neurol. 2014;21(6):851–859.

 PubMed Web of Science ®Google Scholar

Winner PK, Blumenfeld AM, Eross EJ, et al. Long-Term Safety and Tolerability of OnabotulinumtoxinA Treatment in Patients with Chronic Migraine: results of the COMPEL Study. Drug Saf. 2019;42(8):1013–1024.

 PubMed Web of Science ®Google Scholar

Matharu M, Pascual J, Remahl IN, et al. Utilization and safety of onabotulinumtoxinA for the prophylactic treatment of chronic migraine from an observational study in Europe. Cephalalgia. 2017;37(14):1384–1397.

 PubMed Web of Science ®Google Scholar