Tolerability and safety of novel half milliliter formulation of glatiramer acetate for subcutaneous injection: an open-label, multicenter, randomized comparative study

Abstract

Daily glatiramer acetate (GA) 20 mg/1.0 mL is a first-line treatment for relapsing-remitting multiple sclerosis (RRMS). To reduce the occurrence of injection pain and local injection site reactions (LISRs), a reduced volume formulation of GA was developed. This study compared pain and LISRs after injecting the marketed and the novel formulations. RRMS patients currently injecting GA participated in this multicenter, randomized, crossover comparative study. All patients administered once-daily subcutaneous injections of GA 20 mg/1.0 mL (marketed formulation) or GA 20 mg/0.5 mL (reduced volume formulation) for 14 days. Patients were crossed-over to the alternate treatment for an additional 14 days. Using a Visual Analog Scale (VAS), patients recorded in daily diaries the severity of injection pain immediately and 5 min post-injection, and the presence and severity of LISRs (swelling, redness, itching, lump) within 5 min and 24 h post-injection. VAS pain scores were ranked significantly lower immediately and 5 min after GA 20 mg/0.5 mL injections (p < 0.0001). Although LISRs were rare for both preparations, the severity of reactions ranked significantly lower and fewer symptoms occurred within 5 min and 24 h of using the reduced volume formulation (p < 0.0001). GA injected subcutaneously in a reduced volume formulation is a more tolerable option.

Fig. 1

VAS total pain scores (mean + SEM) recorded immediately and 5 min after injection of 20 mg/0.5 mL GA or 20 mg/1.0 mL GA. ^aAs indicated on the Y axis, the rating scale for VAS total pain scores was 0 “no pain” to 100 mm “worst possible pain.” *p < 0.0001; 20 mg/0.5 mL LS mean 133.6 mm, 95% CI 120.0–147.2; and 20 mg/1.0 mL LS mean 154.7 mm, 95% CI 141.0–168.3. ^† p < 0.0001; 20 mg/0.5 mL LS mean 130.4 mm, 95% CI 116.9–143.9; and 20 mg/1.0 mL LS mean 157.6 mm, 95% CI 144.1–171.2

Fig. 2

Daily mean (±SEM) immediate pain scores after injection of 20 mg/0.5 mL GA or 20 mg/1.0 mL GA. ^aAs indicated on the Y axis, the rating scale for VAS total pain scores was 0 “no pain” to 100 mm “worst possible pain.”

Fig. 3

Mean (±SEM) occurrence of LISRs 5 min and 24 h after injection of 20 mg/0.5 mL GA or 20 mg/1.0 mL GA. ^aAs indicated on the Y axis, the presence of symptoms scores could range from 0 “no symptoms” to 4 “all four symptoms occurred.” *p < 0.0001; 20 mg/0.5 mL LS mean 126.2 symptoms, 95% CI 112.9–139.6; and 20 mg/1.0 mL LS mean 161.3 symptoms, 95% CI 147.9–174.7. ^† p < 0.0001; 20 mg/0.5 mL LS mean 132.0 symptoms, 95% CI 118.5–145.6; and 20 mg/1.0 mL LS mean 155.8 symptoms, 95% CI 142.2–169.3

Fig. 4

Mean (±SEM) LISR total severity score 5 min and 24 h after injection of 20 mg/0.5 mL GA or 20 mg/1.0 mL GA. ^aAs indicated on the Y axis, LISR total severity scores could range from 0 to 12 per patient depending on the severity (0 “none” to 3 “severe”) for each of the four LISRs experienced: redness, itching, swelling and lump. *p < 0.0001; 20 mg/0.5 mL LS mean 125.3, 95% CI 112.0–138.6; and 20 mg/1.0 mL LS mean 162.2, 95% CI 148.9–175.6. ^† p < 0.0001; 20 mg/0.5 mL LS mean 132.0, 95% CI 118.5–145.6; and 20 mg/1.0 mL LS mean 155.8, 95% CI 142.2–169.3

Fig. 5

Percentage of patients reporting no LISR symptoms 5 min and 24 h after injection of 20 mg/0.5 mL GA or 20 mg/1.0 mL GA on days 0–3, days 4–6, days 7–9, and days >9