You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Introduction
============

Currently, according to the third beta edition of the International Classification of Headache Disorders revised (ICHD-3 beta) criteria, chronic migraine (CM) is characterized by headache occurring on ≥15 days per month for at least 3 months, which has the features of migraine headache on at least 8 days per month [@b1]. CM is a complex and debilitating neurological disorder [@b2]--[@b4], with a prevalence of 1.4%--2.2% [@b5]. At present, prophylactic treatment options are limited; only onabot-ulinumtoxinA and topiramate have been evaluated in CM patients [@b6]--[@b10], and only onabotulinumtoxinA is specifically indicated for the prophylaxis of headache in patients with CM [@b11].

Results from two exploratory phase 2 studies in patients with chronic daily headache suggested the efficacy of onabotulinumtoxinA within the CM subgroup, which represented the predominant population enrolled in these studies [@b12],[@b13]. In the phase 2 studies, onabotulinumtoxinA was shown to be safe and well tolerated in doses ranging from 75 to 260 U repeated at approximately 12-week intervals for up to three cycles [@b12],[@b13]. More recently, two large-scale, placebo-controlled, multicenter trials (PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy) found onabotulinumtoxinA to be effective in the prophylaxis of CM. These studies demonstrated statistically significant and clinically meaningful improvements compared with placebo in headache day frequency and multiple other headache symptom measures. OnabotulinumtoxinA treatment also significantly reduced headache-related disability and improved functioning, vitality and overall health-related quality of life in patients treated with onabotulinumtoxinA compared with placebo. Furthermore, PREEMPT found that repeated treatment with 155--195 U of onabotulinumtoxinA every 12 weeks over 56 weeks (up to five treatment cycles) was safe and well tolerated [@b6]--[@b8],[@b14].

The present analysis reports on the pooled safety data from the two exploratory phase 2 studies [@b12],[@b13] and the two PREEMPT trials [@b6]--[@b8],[@b14]. These trials enrolled similar patient populations and were subject to similar methodology and adverse event (AE) reporting requirements, allowing the pooling of data for analysis. Analyzing the pooled safety data from the four trials increases statistical power to detect trends in AE incidence that may not have been evident in the individual analyses, and as such sheds light on the safety and tolerability of up to five cycles of onabotulinumtoxinA in adult patients with CM.

Methods
=======

Trial selection and subjects
----------------------------

Patients were men or women aged 18--65. Phase 2 participants experienced chronic daily headache, most commonly caused by CM, with headaches on \>15 days during the 30-day baseline screening [@b12],[@b13]. Patients in the PREEMPT studies had a history of migraine meeting ICHD-2 criteria [@b15],[@b16], except for 'complicated migraine'. During the 28-day baseline, these patients were required to have had ≥15 headache days, of which ≥50% were migraine or probable migraine days, and ≥4 distinct headache episodes, each lasting ≥4 h. Excluded subjects had headache prophylactic medication use within 4 weeks prior to or during baseline, previous exposure to any botulinum toxin serotype or a positive urine pregnancy test [@b8].

Trial design
------------

The PREEMPT 1 and 2 multicenter trials included a 24-week, randomized, double-blind, placebo-controlled (DBPC), parallel-group phase, followed by a 32-week, open-label extension (Fig.[1](#fig01){ref-type="fig"}). After the 4-week baseline, patients were randomized (1:1) to onabotulinumtoxinA (155--195 U) or placebo at day 0 and week 12 (DB phase). Treatments were administered intramuscularly (IM) as 31 fixed-site, fixed-dose (FSFD) injections across seven specific head/neck muscle areas [@b17]. At the investigator\'s discretion, an additional 40 U of onabotulinumtoxinA or placebo could be administered unilaterally or bilaterally, using a 'follow-the-pain' injection paradigm that varied across treatment visits. The maximum dose was 195 U across 39 sites per treatment cycle (Table S1) [@b8]. Patients who completed the DB phase entered the open-label phase, where they received 155--195 U of onabotulinumtoxinA at 12-week intervals, according to the paradigm described above (weeks 24, 36 and 48).

![Schematic of trial designs.](ene0021-0851-f1){#fig01}

The phase 2 trials were multicenter, randomized, DBPC, parallel-group studies of three injection cycles given at 90-day intervals (Fig.[1](#fig01){ref-type="fig"}). After the 30-day baseline, patients were injected with placebo and followed for a 30-day placebo run-in period. They were then randomized and stratified according to their placebo-response status. In the first phase 2 trial [@b12], 105--260 U of onabotulinumtoxinA or placebo was administered IM over six to seven muscle areas. In each treatment cycle, patients received the minimum required dose of 105 U administered as FSFD injections across six muscle groups. Additional 'follow-the-pain' doses were injected at the investigator\'s discretion, based on the location and severity of pain. In the second phase 2 trial [@b13], patients received 20 bilateral FSFD IM injections of 75, 150 or 225 U of onabotulinumtoxinA or placebo across seven specific muscle areas in all treatment cycles (Table S1).

Safety assessments included spontaneously reported AEs, clinical laboratory tests, vital signs, physical examinations and urine pregnancy tests. All AEs were monitored and recorded throughout the study. Serum samples for toxin-neutralizing antibody titer analysis were collected at exit from both phase 2 studies and analyzed using the mouse protection bioassay.

All four studies were conducted in compliance with the ethical principles that originated in the Declaration of Helsinki regarding biomedical research on human subjects and informed consent regulations. Each investigator obtained approval from an independent ethics committee or a local institutional review board prior to study initiation.

Data analysis
-------------

Patient demographics, medical history, onabotulinumtoxinA doses and AEs were pooled and summarized with descriptive statistics. AEs were summarized for each organ system class and preferred term using MedDRA version 11 [@b18]. All patients were counted only once for each AE when multiple occurrences of the same AE were reported, except that in the by-treatment-cycle analysis each new onset of an AE was counted in the cycle in which it started. An ongoing AE was not counted in subsequent cycles unless it worsened. Serious AEs were any that resulted in death, a life-threatening event, hospitalization (initial or prolonged), disability, a congenital anomaly or a medical event that could require medical or surgical intervention to prevent the above outcomes.

Results
=======

Patient demographics, baseline headache characteristics and exposure
--------------------------------------------------------------------

Baseline characteristics are consistent with published reports on CM patients: predominantly middle age (mean 42 years), Caucasian (91%) females (85%) who have had frequent migraine for approximately 20 years (Table [1](#tbl1){ref-type="table"}) [@b2]. Of 2436 patients in the phase 2 and PREEMPT studies, 1997 received at least one onabotulinumtoxinA treatment, providing 16 926 patient-months of exposure; 1448 patients received three treatment cycles or fewer and 513 completed five treatment cycles of onabotulinumtoxinA. Most patients (77.6%) received an initial dose of 150--200 U; per-cycle mean and median onabotulinumtoxinA doses were 163 and 158.3 U, respectively.

###### 

Baseline demographics

  Demographic characteristic                                                                      OnabotulinumtoxinA (*N* = 1384)   Placebo (*N* = 1052)
  ----------------------------------------------------------------------------------------------- --------------------------------- ----------------------
  Age (years), mean ± SD                                                                          42.1 ± 10.34                      42.3 ± 10.89
  Female, *n* (%)                                                                                 1196 (86.4)                       878 (83.5)
  Caucasian, *n* (%)                                                                              1262 (91.2)                       952 (90.5)
  Body mass index (kg/m^2^), mean ± SD                                                            26.60 ± 6.145                     26.94 ± 6.362
  Time since onset of frequent migraine (years),[a](#tf1-1){ref-type="table-fn"} mean ± SD        20.1 ± 12.55                      19.8 ± 12.89
  Age of onset of frequent migraine (years),[b](#tf1-2){ref-type="table-fn"} mean ± SD            21.0 ± 11.09                      21.6 ± 11.79
  Baseline use of acute headache medication -- yes, *n* (%)                                       1332 (96.2)                       1008 (95.8)
  Baseline overuse of acute headache medication -- yes,[c](#tf1-3){ref-type="table-fn"} *n* (%)   897 (64.8)                        693 (65.9)
  Prior headache prophylactic medication use -- yes, *n* (%)                                      745 (53.8)                        609 (57.9)

SD, standard deviation.

Time since onset was calculated from date of onset to day of patient\'s first injection (day 0).

Age of onset was calculated from birth date to date of onset.

To qualify for acute headache medication overuse, a patient had to take this type of medication at least twice per week in any week with at least 5 diary days and for at least 10--15 days during the baseline period (varying with medication category).

Safety
------

### Adverse events

The majority (72.9%) of patients with onabotulinumtoxinA exposure reported at least one AE. The frequency of AEs was higher with onabotulinumtoxinA than with placebo (71.4% vs. 56.8%) during the DB phase (Table [2](#tbl2){ref-type="table"}). The most frequently reported AEs were musculoskeletal in origin (Fig. S1).

###### 

Adverse events reported in ≥2% of patients

                                       DBPC exposure                
  ------------------------------------ --------------- ------------ -------------
  Overall, *n* (%)                     988 (71.4)      598 (56.8)   1455 (72.9)
   Neck pain                           191 (13.8)      25 (2.4)     252 (12.6)
   Muscular weakness                   127 (9.2)       3 (0.3)      160 (8.0)
   Headache                            111 (8.0)       58 (5.5)     142 (7.1)
   Facial paresis                      109 (7.9)       1 (0.1)      122 (6.1)
   Musculoskeletal stiffness           99 (7.2)        14 (1.3)     122 (6.1)
   Upper respiratory tract infection   84 (6.1)        66 (6.3)     127 (6.4)
   Sinusitis                           76 (5.5)        47 (4.5)     134 (6.7)
   Injection site pain                 68 (4.9)        28 (2.7)     89 (4.5)
   Musculoskeletal pain                65 (4.7)        16 (1.5)     89 (4.5)
   Nasopharyngitis                     65 (4.7)        49 (4.7)     118 (5.9)
   Eyelid ptosis                       63 (4.6)        5 (0.5)      91 (4.6)
   Nausea                              51 (3.7)        29 (2.8)     73 (3.7)
   Migraine                            53 (3.8)        25 (2.4)     88 (4.4)
   Bronchitis                          45 (3.3)        22 (2.1)     65 (3.3)
   Muscle tightness                    43 (3.1)        3 (0.3)      71 (3.6)
   Myalgia                             39 (2.8)        9 (0.9)      58 (2.9)
   Hypoaesthesia facial                38 (2.7)        4 (0.4)      41 (2.1)
   Influenza                           35 (2.5)        31 (2.9)     59 (3.0)
   Dizziness                           33 (2.4)        17 (1.6)     53 (2.7)
   Depression                          27 (2.0)        22 (2.1)     43 (2.2)

DBPC, double-blind, placebo-controlled.

The number of patients who received any onabotulinumtoxinA injections during the study, including original placebo patients who received onabotulinumtoxinA in the open-label phase.

During the DB phase, neck pain was the most frequently reported AE in the onabotulinumtoxinA group (13.8% vs. 2.4% with placebo) (Table [2](#tbl2){ref-type="table"}). Other AEs that were reported by ≥5% of patients and occurred more frequently with onabotulinumtoxinA treatment than with placebo were muscular weakness, headache, facial paresis and musculoskeletal stiffness (Table [2](#tbl2){ref-type="table"}). Most muscular weakness was local to onabotulinumtoxinA injection sites or adjacent muscles in the head, neck or shoulder/upper arm regions. The incidences of infections such as sinusitis were similar between the onabotulinumtoxinA and placebo groups (Table [2](#tbl2){ref-type="table"}). The overall and individual incidence rates of AEs that were considered treatment related by the investigator are displayed in Table S2. The onset, duration and severity of the AEs reported by ≥5% of patients were analyzed and are presented in Table [3](#tbl3){ref-type="table"}. Most of these were mild (15.9%) to moderate (35.6%) in severity. Sixty-seven patients (3.4%) with any onabotulinumtoxinA exposure discontinued the studies due to an AE.

###### 

Onset, duration and severity of adverse events reported by ≥5% of patients in the DBPC phase

                                              DBPC exposure       
  ------------------------------------------- ------------------- -----------------
  Neck pain                                   *N* = 191 (13.8%)   *N* = 25 (2.4%)
   Onset (days since most recent injection)   6.9                 25.5
   Duration (days)                            24.3                14.4
   Severity, *n* (%)                                              
    Mild                                      42 (22.0)           2 (8)
    Moderate                                  116 (60.7)          19 (76)
    Severe                                    36 (18.8)           4 (16)
  Muscular weakness                           *N* = 127 (9.2%)    *N* = 3 (0.3%)
   Onset (days since most recent injection)   4.9                 33
   Duration (days)                            30.2                8
   Severity, *n* (%)                                              
    Mild                                      47 (37)             1 (33.3)
    Moderate                                  70 (55.1)           2 (66.7)
    Severe                                    13 (10.2)           0 (0)
  Headache                                    *N* = 111 (8.0%)    *N* = 58 (5.5%)
   Onset (days since most recent injection)   23.9                18.2
   Duration (days)                            26.5                22.3
   Severity, *n* (%)                                              
    Mild                                      22 (19.8)           9 (15.5)
    Moderate                                  51 (45.9)           26 (44.8)
    Severe                                    37 (33.3)           23 (39.7)
  Facial paresis                              *N* = 109 (7.9%)    *N* = 1 (0.1%)
   Onset (days since most recent injection)   5.5                 0
   Duration (days)                            55.6                15
   Severity, *n* (%)                                              
    Mild                                      64 (58.7)           1 (100)
    Moderate                                  36 (33.0)           0 (0)
    Severe                                    7 (6.4)             0 (0)
  Musculoskeletal stiffness                   *N* = 99 (7.2%)     *N* = 14 (1.3%)
   Onset (days since most recent injection)   6.1                 33.9
   Duration (days)                            20.8                17.2
   Severity, *n* (%)                                              
    Mild                                      37 (37.4)           5 (35.7)
    Moderate                                  60 (60.6)           8 (57.1)
    Severe                                    8 (8.1)             1 (7.1)
  Upper respiratory tract infection           *N* = 84 (6.1%)     *N* = 66 (6.3%)
   Onset (days since most recent injection)   52.8                49.6
   Duration (days)                            13.1                15.6
   Severity, *n* (%)                                              
    Mild                                      41 (48.8)           25 (37.9)
    Moderate                                  40 (47.6)           33 (50.0)
    Severe                                    5 (6.0)             10 (15.2)
  Sinusitis                                   *N* = 76 (5.5%)     *N* = 47 (4.5%)
   Onset (days since most recent injection)   47                  40.2
   Duration (days)                            16.6                18.2
   Severity, *n* (%)                                              
    Mild                                      26 (34.2)           14 (29.8)
    Moderate                                  43 (56.6)           27 (57.4)
    Severe                                    9 (11.8)            7 (14.9)

DBPC, double-blind, placebo-controlled.

### Deaths and serious adverse events

One death was reported in the placebo group in one of the phase 2 studies. This event was considered to be due to 'cardiac irregularity' and was determined to be unrelated to the study treatment. Serious AEs were reported for 4.7% of onabotulinumtoxinA patients and 3.0% of placebo patients during the DB phase. The most frequently reported serious AE was migraine, followed by pneumonia, uterine leiomyoma and headache (Table [4](#tbl4){ref-type="table"}). Amongst the 1997 patients with any onabotulinumtoxinA exposure, serious AEs were reported in 5.4% (*n* = 107) of patients. The most frequently reported serious AEs were the same as for the DBPC phase (Table [4](#tbl4){ref-type="table"}).

###### 

Serious adverse events reported by more than two patients

                                    DBPC exposure              
  --------------------------------- --------------- ---------- -----------
  Overall, *n* (%)                  65 (4.7)        32 (3.0)   107 (5.4)
   Migraine                         5 (0.4)         1 (0.1)    9 (0.5)
   Pneumonia                        3 (0.2)         2 (0.2)    5 (0.3)
   Uterine leiomyoma                3 (0.2)         1 (0.1)    6 (0.3)
   Headache                         3 (0.2)         0 (0.0)    3 (0.2)
   Appendicitis                     2 (0.1)         1 (0.1)    2 (0.1)
   Cholelithiasis                   2 (0.1)         1 (0.1)    2 (0.1)
   Breast cancer                    2 (0.1)         0 (0.0)    3 (0.2)
   Major depression                 2 (0.1)         0 (0.0)    2 (0.1)
   Endometriosis                    1 (0.1)         3 (0.3)    1 (0.1)
   Intervertebral disc protrusion   1 (0.1)         2 (0.2)    2 (0.1)
   Basal cell carcinoma             1 (0.1)         1 (0.1)    2 (0.1)
   Abdominal pain upper             1 (0.1)         0 (0.0)    2 (0.1)
   Calculus ureteric                1 (0.1)         0 (0.0)    2 (0.1)
   Cholecystitis                    1 (0.1)         0 (0.0)    2 (0.1)
   Depression                       1 (0.1)         0 (0.0)    2 (0.1)
   Nephrolithiasis                  1 (0.1)         0 (0.0)    2 (0.1)
   Small intestinal obstruction     0 (0.0)         1 (0.1)    2 (0.1)

DBPC, double-blind, placebo-controlled.

###### 

Number (%) of patients with adverse events reported by ≥5% of patients in any dose group in the DBPC phase

                                       OnabotulinumtoxinA dose group                             
  ------------------------------------ ------------------------------- ------------ ------------ ------------
  Overall, *n* (%)                     157 (83.1)                      624 (66.6)   207 (80.2)   598 (56.8)
   Neck pain                           35 (18.5)                       104 (11.1)   52 (20.2)    25 (2.4)
   Muscular weakness                   24 (12.7)                       62 (6.6)     41 (15.9)    3 (0.3)
   Upper respiratory tract infection   23 (12.2)                       45 (4.8)     16 (6.2)     66 (6.3)
   Headache                            21 (11.1)                       59 (6.3)     31 (12.0)    58 (5.5)
   Musculoskeletal stiffness           20 (10.6)                       46 (4.9)     33 (12.8)    14 (1.3)
   Sinusitis                           15 (7.9)                        48 (5.1)     13 (5.0)     47 (4.5)
   Facial paresis                      15 (7.9)                        47 (5.0)     47 (18.2)    1 (0.1)
   Nausea                              13 (6.9)                        28 (3.0)     10 (3.9)     29 (2.8)
   Musculoskeletal pain                11 (5.8)                        39 (4.2)     15 (5.8)     16 (1.5)
   Nasopharyngitis                     11 (5.8)                        38 (4.1)     16 (6.2)     49 (4.7)
   Bronchitis                          11 (5.8)                        24 (2.6)     10 (3.9)     22 (2.1)
   Injection site pain                 10 (5.3)                        38 (4.1)     20 (7.8)     28 (2.7)
   Arthralgia                          10 (5.3)                        14 (1.5)     6 (2.3)      13 (1.2)
   Eyelid ptosis                       7 (3.7)                         40 (4.3)     16 (6.2)     5 (0.5)
   Muscle tightness                    7 (3.7)                         19 (2.0)     17 (6.6)     3 (0.3)
   Hypoesthesia facial                 7 (3.7)                         12 (1.3)     19 (7.4)     4 (0.4)

DBPC, double-blind, placebo-controlled.

### Adverse events by treatment cycle

To assess AE incidence for each onabotulinumtoxinA cycle and the effect of multiple treatments over time, PREEMPT patients who completed all five treatment cycles (*n* = 513) were analyzed. Due to a lack of available data in five treatment cycles following a standardized protocol over a limited dose range, the phase 2 studies were excluded from this analysis. The overall incidence of AEs decreased from 48.3% in the first cycle to 19.1% in the fifth cycle. The majority of the individual AEs (≥2%) decreased in subsequent treatment cycles, as displayed in Fig.[2](#fig02){ref-type="fig"}. When taking the entire PREEMPT population into account (*n* = 1384), the decreased incidence of AEs was not due to discontinuations, as the discontinuation rates per treatment cycle were similar (cycle 1, 5.4%; cycle 2, 5.3%; cycle 3, 5.7%; cycle 4, 6.3%; cycle 5, 4.7%).

![Adverse events reported by ≥2% of patients who completed five cycles of onabotulinumtoxinA treatment per treatment cycle, including subjects who received onabotulinumtoxinA at all five injection cycles and completed the study.](ene0021-0851-f2){#fig02}

### Adverse events by dose

When compared by dose ranges, overall AEs were similar in the \<150 U group (83.1%) and the \>200 U group (80.2%) but lower in the 150--200 U group (66.6%) (Table [5](#tbl5){ref-type="table"}). Neck pain was the most frequently occurring AE, with an incidence of 18.5%, 11.1% and 20.2%, respectively, in the three dose groups (from low to high) (Table [5](#tbl5){ref-type="table"}). The same incidence pattern was observed for the other frequently reported AEs, i.e. muscular weakness, musculoskeletal stiffness and headache.

### Laboratory evaluations, vital signs and physical examinations

There were no clinically meaningful mean changes or shifts in laboratory parameters, vital signs (including systolic or diastolic blood pressure, pulse rate and temperature) or physical examinations. For laboratory parameters with both lower and upper limit potential abnormalities, both decreases and increases were observed in the mean parameter values, indicating incidental fluctuations.

### Hypersensitivity, immunogenicity and possible distant muscle weakness

The overall incidence of AEs potentially associated with hypersensitivity (e.g. urticaria, seasonal allergy and eyelid edema) in patients with any onabotulinumtoxinA exposure was low (2.5%) and similar to that reported by patients during the DB phase (2.2% onabotulinumtoxinA and 2.0% placebo). None of these AEs was considered treatment related.

Immunogenicity and antibody formation after onabotulinumtoxinA treatments were evaluated for toxin-neutralizing antibodies from serum samples collected in phase 2 studies. There were no positive toxin-neutralizing antibodies, and one patient had inconclusive results. Assessment of immunogenicity was not conducted in the PREEMPT clinical program because there were sufficient data from the phase 2 studies that demonstrated no heightened risk for immunogenicity in the CM population [@b8]. Possible distant muscle weakness AEs were assessed by an in-depth medical evaluation of each case performed according to a standard approach [@b19] using 40 MedDRA terms potentially reflective of distant spread. It was determined that none of these AEs was due to distant spread of toxin.

Discussion
==========

This pooled analysis supports onabotulinumtoxinA safety and tolerability for headache prophylaxis in adult patients with CM. Multiple onabotulinumtoxinA treatments were safe and well tolerated, with low AE-related discontinuation rates. In the DBPC phase, the overall AE rate for onabotulinumtoxinA-treated patients was lower in the PREEMPT population (62.4%) [@b8] compared with the pooled CM safety population (71.4%). Individual AE rates for onabotulinumtoxinA-treated patients, such as neck pain (9% vs. 14%), muscle weakness (4% vs. 9%), headache (5% vs. 8%) and facial paresis (2% vs. 8%), were also lower in the PREEMPT clinical program [@b11] compared with the pooled CM safety population, respectively. This reduction in AE incidence probably reflects the optimized dosing regimen, injection paradigm, experience of the injectors in the trial, and modified injection sites used in PREEMPT [@b8],[@b12],[@b13],[@b17].

Focally administered onabotulinumtoxinA inhibits the release of acetylcholine at the neuromuscular junction and has been used therapeutically in disorders characterized by muscle hyperactivity [@b20],[@b21]. Muscular weakness, eyelid ptosis and facial paresis are thus expected side effects of onabotulinumtoxinA due to its action on muscle activity and were amongst the most frequently reported AEs. Most of the muscular weakness was local to the head, neck or shoulder/upper arm regions, which involved either the injected muscles or adjacent muscles. Weakness of nearby muscles may also occur due to local diffusion; however, distant effects were not reported.

Headache and migraine were frequently (≥2%) reported AEs; they occurred more often with onabotulinumtoxinA (8.0% and 3.8%, respectively) than with placebo (5.5% and 2.4%, respectively), although the distribution of headache severity was similar between the two groups (Table [3](#tbl3){ref-type="table"}). Additionally, for the subset of patients that completed all five treatment cycles of the PREEMPT clinical program, the incidence of migraine and headache decreased after the first treatment cycle (Fig.[2](#fig02){ref-type="fig"}). Patients treated with onabotulinumtoxinA did not have a worsening of headache or migraine, and the onabotulinumtoxinA-treated patients in the PREEMPT clinical program [@b8] experienced significant improvements in multiple headache symptom measures compared with those treated with placebo.

The chronic nature of CM requires repeated treatments, and thus the long-term safety of onabotulinumtoxinA treatment is an important consideration. For other conditions, treatment also requires long-term, repeated, multi-muscle injection of onabotulinumtoxinA in the head/neck areas. A 10-year multicenter study of onabotulinumtoxinA treatment for primary hemifacial spasm showed that the rate of local AEs (including upper lid ptosis, facial weakness and diplopia) diminished significantly in the tenth year of treatment compared with the first year, whilst efficacy was maintained [@b22]. In a long-term cervical dystonia study [@b23], 326 patients were treated with up to 15 onabotulinumtoxinA treatments (median 9), and mean dose per session ranged from 148 to 213 U over a mean of 2.5 years (range 3.2 months to 4.2 years). The incidence of muscular weakness and dysphagia, the two most commonly reported AEs, decreased with repeat injection sessions. Our analysis shows that no new safety findings emerged in patients receiving onabotulinumtoxinA long-term treatment over 56 weeks compared with the first treatment cycle, suggesting that there is no cumulative toxicity with long-term onabotulinumtoxinA use.

Although not specifically indicated for CM, other currently prescribed treatments can have significant treatment-limiting, systemic AEs. Antiepileptics are associated with systemic AEs including gastrointestinal problems, somnolence, difficulty with concentration/attention, nervousness, alopecia, tremor, liver toxicity and paresthesia. Beta-blockers are associated with depression, fatigue, dizziness, sexual dysfunction and sleep disturbances [@b24].

In the only other large DBPC study in CM (*n* = 328), which compared topiramate with placebo for CM [@b9], AEs were reported by the majority of patients in both treatment groups (82.5% topiramate vs. 70.2% placebo). The most common AEs associated with topiramate were paresthesia (28.8% vs. 7.5% placebo), upper respiratory tract infection (13.8% vs. 12.5% placebo) and fatigue (11.9% vs. 9.9% placebo). Additional AEs occurring in \>5% of the topiramate-treated patients were hypoesthesia, dry mouth, difficulty with concentration or memory, taste perversion, nausea and somnolence [@b9]. In a small pilot study of CM prophylaxis (*n* = 60) comparing onabotulinumtoxinA (two IM injections of 100--200 U every 12 weeks) and topiramate (100--200 mg/day), efficacy results were comparable. However, fewer treatment-related AEs were reported with onabotulinumtoxinA (69.2%) than with topiramate (86.2%). A greater percentage of topiramate-treated than onabotulinumtoxinA-treated patients (24.1% vs. 7.7%, respectively) discontinued the study due to treatment-related AEs [@b25].

Side-effect profiles may vary amongst different botulinum neurotoxin preparations [@b26]. Safety information in the present analysis is specific to the formulation of onabotulinumtoxinA manufactured by Allergan Inc. and cannot be generalized to other botulinum neurotoxin preparations or serotypes.

Conclusions
===========

This pooled analysis of four DBPC trials confirms the favorable safety and tolerability profile of repeated treatment with onabotulinumtoxinA (five cycles over 56 weeks; 75--260 U) for the prophylaxis of headache in adults with CM.

Clinical experience and optimal muscle targeting is important in improving the safety and tolerability profile in onabotulinumtoxinA treatment [@b26]. Our analysis shows that the dosing and injection paradigm used in the PREEMPT clinical program (155--195 U), which resulted in fewer individual AEs in addition to demonstrating robust long-term (up to 56 weeks) efficacy [@b6]--[@b8],[@b14], is preferred for this CM patient population.

The authors thank Allergan Inc. for funding support in copyediting of this manuscript, provided by Marissa Nolan, PhD, of Imprint Publication Science, New York, NY.

Disclosure of conflicts of interest
===================================

H-C Diener received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Addex Pharma, Allergan, Almirall, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Böhringer Ingelheim, Bristol-Myers Squibb, Coherex, CoLucid, GlaxoSmithKline, Grünenthal, Janssen-Cilag, Lilly, La Roche, 3M Medica, Medtronic, Menerini, Minster, MSD, Neuroscore, Novartis, Johnson & Johnson, Pierre Fabre, Pfizer, Schaper and Brümmer, Sanofi, St Jude and Weber & Weber. He has received financial support for research projects from Allergan, Almirall, AstraZeneca, Bayer, GSK, Janssen-Cilag, MSD and Pfizer. Headache research at the Department of Neurology in Essen is supported by the German Research Council (DFG), the German Ministry of Education and Research (BMBF) and the European Union. Dr Diener has no ownership interest and does not own stocks of any pharmaceutical company. DW Dodick has served on advisory boards for, consulted for, or received funding for travel, speaking or editorial activities from the following: Allergan, Amgen, Alder, Arteaus, Atlas, Pfizer, Merck, Ferring, Neurocore, Neuraxon, NuPathe, SmithKline Beecham, Boston Scientific, Medtronic Inc., Nautilus, Eli Lilly & Company, Novartis, Colucid, Autonomic Technologies, MAP Pharmaceuticals Inc., Zogenix Inc., Impax Laboratories Inc., E-Neura, Labry\'s, Johnson & Johnson, Ethicon J&J, Nevro Corp., St Jude, Gore, Synergy, Ogilvy and Y&R. He serves as Editor-in-Chief and on the editorial boards of *The Neurologist*, *Lancet Neurology* and *Postgraduate Medicine*; and has served as Editor-in-Chief of *Headache Currents* and as an Associate Editor of *Headache*. He receives publishing royalties for *Wolff\'s Headache*, 8th edn (Oxford University Press, 2009), and *Handbook of Headache* (Cambridge University Press, 2010). CC Turkel, G Demos, RE DeGryse, NL Earl and MF Brin are employees of Allergan Inc.

Supporting Information
======================

Additional Supporting Information may be found in the online version of this article:

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**Figure S1.** Adverse events reported in ≥2% of patients clustered by system organ class.

**Table S1.** Summary of studies.

**Table S2.** Treatment-related adverse events reported in ≥2% of patients.

[^1]: \[Correction added on 9 April 2014 after first online publication: article was made Open Access and copyright line was amended.\]