# Abstract

 

## Objective To evaluate the efficacy, tolerability, and safety of once-daily 1200 mg and 2400 mg SPN-804 (Oxtellar XR™, Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization. 

## Methods The Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double-blind, parallel-group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week double-blind treatment period in the intent-to-treat (ITT) population with analyzable seizure data. Other efficacy analyses included proportion of patients with ≥ 50% seizure reduction, proportion of patients seizure free, and the relationship between clinical response and plasma concentration. 

## Results Median percent reduction was -28.7% for placebo, −38.2% (\*P *=* \*0.08 vs placebo) for once-daily SPN-804 1200 mg, and −42.9% (\*P *=* \*0.003) for SPN-804 2400 mg. Responder rates were 28.1%, 36.1% (\*P *=* \*0.08), and 40.7% (\*P *=* \*0.02); 16-week seizure-free rates in a pragmatic ITT analysis were 3.3%, 4.9% (\*P *=* \*0.59), and 11.4% (\*P *=* \*0.008), respectively. When data were analyzed separately for study site clusters, a *post hoc* analysis demonstrated that both SPN-804 dosages were significantly superior to placebo in median percent seizure reduction (placebo: −13.3%; 1200 mg: −34.5%, \*P *=* \*0.02; 2400 mg: −52.7%, \*P *=* \*0.006) in the North American study site cluster. A concentration--response analysis also supported a clinically meaningful effect for 1200 mg. Adverse event types reflected the drug's established profile. Adverse event frequency was consistent with a pharmacokinetic profile in which SPN-804 produces lower peak plasma concentrations vs immediate-release OXC. Once-daily dosing was not associated with any new safety signals. 

## Conclusions Adjunctive once-daily SPN-804 improved seizure control in patients with inadequately controlled partial-onset seizures. Adverse event occurrence and discontinuations due to adverse events suggest improved tolerability vs previously published data with immediate-release OXC. # Results 

## Patient disposition and characteristics Of 440 patients screened, 366 patients were randomized to once-daily placebo (\*n *=* \*121), SPN-804 1200 mg (\*n *=* \*122), and SPN-804 2400 mg (\*n \*= 123). Analyzable seizure data for the primary efficacy analysis were available for 96.7% (\*n *=* \*117), 89.3% (\*n *=* \*109), and 90.3% (\*n *=* \*111), respectively (Fig. [1](#)). Of the 111 patients in the 2400-mg group with analyzable seizure data, 26 were patients in whom SPN-804 was down-titrated to 1800 mg/day. Overall, 67.8% of patients completed 16 weeks, with 21.5% of placebo patients discontinuing prematurely compared with 32.8% and 42.3% in the 1200-mg and 2400-mg SPN-804 groups, respectively. The most common reason for study withdrawal was adverse events, accounting for the higher discontinuation rates in the active treatment groups. Based on pill counts, 96.0% (placebo), 93.2% (1200 mg), and 95.1% (2400 mg) of patients were adherent with once-daily dosing. <figure> <p><img src="" /></p> <figcaption>Study disposition for patients assigned to placebo or Oxtellar XR (SPN-804).</figcaption> </figure> Treatment groups were generally well balanced in terms of baseline demographics and disease characteristics (Table [1](#)). Overall, the mean age was 38.9 years; 55.2% of patients were women. The mean number of years since epilepsy diagnosis was 20.8 years; median monthly seizure frequency at baseline was 6.5 seizures despite ongoing treatment with two or three concomitant AEDs in 67.2% of patients. ::::table-wrap

::: caption
Demographics and baseline characteristics (safety population)
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Characteristics Placebo (\*N = \*121) Oxtellar XR (SPN-804), mg/day

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1200 (\*N *=* \*122) 2400 (\*N *=* \*123)\
Age (years), mean ± SD 39.1 ± 12.5 39.1 ± 11.5 38.5 ± 11.6
Female, *n* (%) 67 (55.4) 71 (58.2) 64 (52.0)
Race, *n* (%)\
White 107 (88.4) 104 (85.2) 105 (85.4)
Black 1 (0.8) 5 (4.1) 1 (0.8)
Other 13 (10.7) 13 (10.7) 17 (13.8)
Epilepsy duration (years), mean ± SD 21.2 ± 13.9 21.3 ± 14.5 19.8 ± 13.0
Baseline seizure frequency (seizures/28 days), median 7.0 6.0 6.0
Concomitant AEDs, *n* (%)\
1 AED 43 (35.5) 36 (29.5) 40 (32.5)
2 AEDs 61 (50.4) 68 (55.7) 67 (54.5)
3 AEDs 17 (14.0) 18 (14.8) 16[\*](#) (13.0)
Valproate 49 (37.2) 55 (45.1) 62 (50.4)
Carbamazepine 44 (36.4) 53 (43.4) 49 (39.8)
Lamotrigine 37 (30.6) 31 (25.4) 34 (27.6)
Levetiracetam 27 (22.3) 20 (16.4) 28 (22.8)
Topiramate 21 (17.3) 23 (18.8) 23 (18.7)
Phenytoin 4 (3.3) 3 (2.5) 2 (1.6)
Other 26 (21.5) 29 (23.8) 18 (14.6)

*N*, total number of patients; *n*, number of patients with analyzable
data; SD, standard deviation; AEDs, antiepileptic drugs.

One patient assigned to SPN-804 2400 mg was receiving 4 AEDs.:::: 

## Efficacy The median percent seizure frequency change over the 16-week double-blind treatment period was −28.7% with placebo vs −38.3% (\*P *=* \*0.08) for once-daily 1200-mg and −42.9% (\*P *=* \*0.003) in the 2400-mg group (Fig. [2](#)). The estimated treatment difference favoring SPN-804 over placebo was −10.3% (95% CI: −22.3, 1.2) for 1200-mg and −18.3% (95% CI: −30.4, −5.8) for 2400-mg group. Secondary endpoints generally mirrored the primary efficacy analysis. Responder rates, that is, proportion of patients with ≥50% seizure frequency reduction (Fig. [2](#)), were placebo, 28.1%; 1200 mg, 36.1% (\*P *=* \*0.08); and 40.7% (\*P *=* \*0.02) of those receiving 2400 mg. The odds ratio comparing the responder rates was 1.67 (95% CI: 0.95, 2.94) for SPN-804 1200 mg vs placebo and 1.98 (95% CI: 1.13, 3.50) when comparing 2400 mg and placebo. For the prespecified pragmatic ITT analysis of seizure freedom, 3.3% of the placebo group, 4.9% (\*P *=* \*0.53) in the 1200-mg group, and 11.4% (\*P *=* \*0.008) in the 2400-mg group were seizure free for the entire 16-week blinded treatment period. <figure> <p><img src="" /></p> <figcaption>Oxtellar XR (SPN-804) vs placebo: Median percent reduction from baseline 28-day seizure frequency (A) and responder rate (B) for the 16-week double-blind treatment period in ITT population with analyzable data. \*<em>P </em>=<em> </em>0.003; \*\*<em>P </em>=<em> </em>0.02 vs placebo. ITT, intent-to-treat.</figcaption> </figure> Sensitivity analyses using a completer and a mixed-model repeated-measures analysis did not change the primary statistical outcome that once-daily SPN-804 2400 mg was shown to be significantly superior to placebo, whereas 1200 mg was not. However, in a sensitivity analysis evaluating the potential influence of regional differences in this multinational trial, both SPN-804 dosage groups were significantly superior to placebo in median percent seizure reduction -- placebo, −13.3%; 1200 mg, −34.5% (\*P *=* \*0.02); 2400 mg, −52.7% (\*P *=* \*0.006) among patients (\*n *=* \*106) participating at North American study sites (Fig. [3](#)). The estimated treatment difference favoring SPN-804 over placebo was −26.1% (95% CI: −47.9, −4.1) for 1200-mg and −35.3% (95% CI: −59.1, −12.5) for 2400-mg group. In contrast, with the substantially higher placebo effect (-33.2%) observed in patients (\*n *=* \*231) from the Eastern Europe/Russia study site cluster (Fig. [3](#)), neither SPN-804 dosage group was significantly superior to placebo (1200 mg: −38.4%, \*P *=* \*0.60; 2400 mg: −41.2%, \*P *=* \*0.13) in this subset. <figure> <p><img src="" /></p> <figcaption>Oxtellar XR (SPN-804) vs placebo: Median percent reduction from baseline 28-day seizure frequency in the North American cluster of study sites (A) and Eastern Europe/Russia cluster (B) in the ITT population. \*<em>P </em>=<em> </em>0.02; \*\*<em>P </em>=<em> </em>0.006 vs placebo. ITT, intent-to-treat.</figcaption> </figure> After 16 weeks of double-blind treatment, PGIC score changes were not significantly different for either SPN-804 dosage vs placebo. Mean total QOLIE-31 and subscale scores did not decrease from baseline during SPN-804 or placebo administration in any group. The only significant differences from placebo in QOLIE-31 score changes were significantly smaller increases in the QOLIE-31 subscales of Cognitive Functioning in the 1200-mg and Medication Effects in both SPN-804 groups (\*P *\<* \*0.01 vs placebo). 

## Tolerability and safety The overall incidence of adverse events (Table [2](#)) was similar in the placebo (55.4%) and SPN-804 1200-mg groups (56.6%) and was lower than in patients assigned to 2400 mg (69.1%). The incidences of specific adverse events were generally similar for the placebo and SPN-804 1200-mg groups. The most common adverse events were those related to the nervous system, occurring in 31.4% of placebo patients and 38.5% of those receiving 1200 mg, compared with 56.1% in the 2400-mg group. The most frequently reported adverse events -- dizziness, nausea, somnolence, vomiting, headache, and diplopia -- were typically dose related. Treatment-limiting adverse event rates were 8.3% and 14.8% in the placebo and 1200-mg groups, respectively; 30.1% in the 2400-mg group discontinued due to adverse events. In the active treatment groups, adverse events resulting in discontinuation occurred primarily during the forced-titration phase (1200 mg: 13/20, 65%; 2400 mg: 26/37, 70%). The fact that 23 patients were down-titrated to 1800 mg also suggests some difficulty with tolerability at 2400 mg. ::::table-wrap
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Summary of treatment-emergent adverse events (safety population)
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```
                                                   Placebo (*N *=* *121)   Oxtellar XR (SPN-804), mg/day   
```

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1200 (\*N *=* \*122) 2400 (\*N *=* \*123)\
Any adverse event, *n* (%) 67 (55.4) 69 (56.6) 85 (69.1)
Serious adverse events, *n* (%) 7 (5.8) 7 (5.7) 10 (8.1)
Adverse events leading to discontinuation, *n* (%) 10 (8.3) 18 (14.8) 37 (30.1)
Incidence, *n* (%)\
Dizziness 18 (14.9) 24 (19.7) 50 (40.7)
Vomiting 11 (9.1) 7 (5.7) 19 (15.4)
Headache 9 (7.4) 10 (8.2) 19 (15.4)
Somnolence 11 (9.1) 14 (11.5) 17 (13.8)
Diplopia 5 (4.1) 12 (9.8) 16 (13.0)
Nausea 14 (11.6) 14 (11.5) 15 (12.2)
Asthenia 1 (0.8) 4 (3.3) 9 (7.3)
Balance disorder 6 (5.0) 6 (4.9) 8 (6.5)
Fatigue 1 (0.8) 7 (5.7) 4 (3.3)

*N*, total number of patients; *n*, number of patients.:::: Serious adverse events occurred in seven patients each in the placebo (5.8%) and SPN-804 1200-mg (5.7%) groups and in 10 (8.1%) in the 2400-mg group. Of the adverse events classified as serious, none were considered study drug-related in the SPN-804 1200-mg group and three were considered study drug-related in the placebo group (one subject each with erythematous rash, Stevens--Johnson syndrome, or dizziness). A fourth patient assigned to the placebo group was the only death in the study (death due to ovarian cancer diagnosed 2 days before randomization). Serious adverse events were considered study drug-related in six patients receiving SPN-804 2400 mg -- symptomatic hyponatremia (\*n *=* \*1), generalized rash (\*n *=* \*1), dizziness (\*n *=* \*1), vomiting (\*n *=* \*1), and general drug intolerance (\*n *=* \*2), which was characterized by other non-serious adverse events such as dizziness, diplopia, nausea, vomiting, abdominal pain, and/or headache. Study drug was discontinued in all patients with serious adverse events, although SPN-804 was initially down-titrated in one patient before being discontinued due to vertigo/dizziness. Only one clinically significant laboratory, vital sign, or ECG abnormality was observed during the study. A shift from normal to lower serum sodium levels was observed in a relatively small subset of patients receiving active treatment (placebo, 1.7%; 1200 mg, 9.8%; 2400 mg, 6.5%). Serum sodium levels were < 130 mEq/l at any point during double-blind treatment in nine patients receiving SPN-804 (1200 mg, \*n *=* \*4; 2400 mg, \*n *=* \*5) and < 125 mEq/l in two patients (one in each SPN-804 group). One occurrence of a markedly abnormal sodium value resulted in symptomatic hyponatremia and was classified as a serious adverse event. 

## Pharmacokinetics and pharmacodynamics Based on population PK analysis of plasma MHD concentrations, the mean (SD) C~max~ of MHD was 17.9 (5.3) μg/ml in patients receiving once-daily SPN-804 1200-mg and 27.1 (8.7) μg/ml in the 2400-mg group; C~min~ concentrations were 12.0 (4.3) μg/ml and 19.4 (7.8) μg/ml, respectively. Clearance was increased 31% in patients receiving carbamazepine, phenytoin, phenobarbital, or valproate as concomitant therapy, but was not increased further when more than one of these agents was given as co-therapy. In a concentration--response analysis, patients receiving SPN-804 were grouped according to estimated trough (C~min~) MHD concentrations. The breakpoint between subgroups (10 μg/ml) was determined by a sensitivity analysis. The overall median C~min~ across SPN-804 groups was 13.9 μg/ml. Median percent seizure frequency reduction was significantly greater in the subgroup with C~min~ ≥10 μg/ml MHD (\*n *=* \*125, −50%, \*P *=* \*0.02) compared with the \<10 μg/ml subgroup (\*n *=* \*41, −35.2%) or the placebo group (*n = *117*,* −28.7%, \*P *=* \*0.0004); the difference in median percent change for \<10 μg/ml subgroup vs placebo was not significant (\*P *=* \*0.57). The C~min~ was ≥ 10 μg/ml in approximately 85% of patients in the SPN-804 2400-mg group and 66% in the 1200-mg group.


Extracted trial result:
Outcome: Adverse effects (binary)
Intervention: Extended-release oxcarbazepine 1200 mg
Comparator: Control
Intervention events: 69
Intervention group size: 123
Comparator events: 67
Comparator group size: 122