A Phase IV, Randomized, Double-Blind, Crossover Study to Compare the Clinical Safety and Efficacy of AbobotulinumtoxinA and OnabotulinumtoxinA in Adult Upper Limb Spasticity

Lack of head-to-head comparative safety and efficacy data for abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) represented an important gap for informed spasticity management. This study compared the safety and efficacy of aboBoNT-A and onaBoNT-A for upper limb spasticity (ULS). DIRECTION (NCT04936542), a phase IV, randomized, double-blind, crossover study, involved 72 sites. Patients stratified by botulinum toxin A status (naïve/non-naïve) were randomized (1:1) to aboBoNT-A 900U followed by onaBoNT-A 360U (one cycle each), or vice versa. Muscles (wrist/finger flexors, biceps brachii) were injected with a fixed volume, using instrument-guided injection techniques. Participants fulfilling retreatment criteria received a second cycle at Week 12; otherwise, they were reassessed every 4 weeks (to Week 24) until requiring retreatment. Primary analyses tested non-inferiority based on treatment-emergent adverse events (TEAEs) from injection to Week 12 using a 5% non-inferiority margin [non-inferiority demonstrated if upper bound of the 80% confidence interval (CI) of the adjusted difference in TEAE rates was < 5%]. Secondary analyses compared duration of response based on time to symptom re-emergence. Overall, 464 patients [mean (standard deviation) age 56.8 (13.1) years, 34.1% female] were randomized (aboBoNT-A → onaBoNT-A [n = 231]; onaBoNT-A → aboBoNT-A [n = 233)]. Baseline characteristics were similar in both sequence arms. Adjusted rate of TEAEs for aboBoNT-A (20.3%) was non-inferior to onaBoNT-A (23.0%); adjusted difference (aboBoNT-A – onaBoNT-A) was − 2.7% (80%CI − 6.2%, 0.9%). Adjusted mean duration of response was 99.3 days for aboBoNT-A and 96.3 days for onaBoNT-A; adjusted difference of 3.0 (80%CI 0.2, 5.9) days favoring aboBoNT-A (p = 0.17; statistically significant under the pre-specified α = 0.20 framework). Longer duration of response with aboBoNT-A versus onaBoNT-A was seen across most subgroups over a fixed-interval follow-up. In this first head-to-head study of aboBoNT-A and onaBoNT-A in ULS, the aboBoNT-A TEAE rate was non-inferior to onaBoNT-A. At 90% of the maximum unit dose for adult ULS in the approved label for each formulation, duration of response was 3 days longer with aboBoNT-A than onaBoNT-A. These findings may support informed therapeutic decision-making. ClinicalTrials.gov: NCT04936542; EudraCT: 2023-509196-16-00. Spasticity of the upper limb presents as muscle and limb stiffness that affects the arm and/or hand. It happens when parts of the brain or spinal cord that control movement are damaged. Spasticity can be painful and can make daily activities challenging. Some people with upper limb spasticity receive botulinum toxin A (BoNT-A) injections to help relax the affected muscles. BoNT-A injections work for a period, but retreatment is required when the effects start to wear off. AbobotulinumtoxinA and onabotulinumtoxinA are different types of BoNT-A. DIRECTION is the first-ever spasticity study to compare abobotulinumtoxinA and onabotulinumtoxinA directly in people with upper limb spasticity. It involved 464 people living with spasticity across the USA, France, and Canada. The study population had an average age of 57 years, two-thirds were male, and most had spasticity because of a stroke. The study found that, over the 12 weeks after BoNT-A treatment, similar numbers of patients had side-effects to abobotulinumtoxinA and onabotulinumtoxinA. In addition, it took longer for symptoms to return after treatment with abobotulinumtoxinA (99 days) compared with onabotulinumtoxinA (96 days). Longer BoNT-A treatment duration can reduce the number of days that people with upper limb spasticity have to live with symptoms before their next injection. More symptom-free days could reduce the need for patients and their caregivers to seek additional care and could reduce their overall treatment burden. These findings provide new information to help healthcare professionals make decisions about BoNT-A treatment to achieve the best outcomes for their patients with arm/hand spasticity.