Part I:
Pk Evaluation (See Fig. )
A linear dose response relationship was demonstrated between cohorts #1 (30 mg) and #2 (60 mg), with a factor of two between cohorts. By 90 minutes post-administration, cohorts #1 and #2 achieved an average topiramate plasma concentration of 0.16 µg/ml and 0.3 µg/ml, respectively. These plasma levels were maintained up to 540 minutes after administration. In cohort #3 concentration levels demonstrated a cumulative dose response relationship with an additive increase in concentrations, and achieved a peak average level of 2 µg/ml .
By 24 hours plasma levels showed a decline in all three cohorts, though remained near peak levels.
Adverse Events And Side Effects
There were no adverse events during all 38 administrations in Part 1. There were no significant changes in clinical laboratory tests following SipNose-topiramate administration. General physical and nasal mucosa examinations were normal in all subjects in all cohorts.
One side effect was reported in cohort #1: sore throat (12.5%), which is known topiramate related side effects and do not necessarily result from the combination product.
Two side effects were reported in cohort #2: headache (12.5%) and runny nose (12.5%).
Eleven side effects were reported in cohort #3, in which the highest dose, 180mg was given: dizziness (9.09%), heaviness (4.54%), mood changes (4.54%), tiredness (4.54%), headache (4.54%), flu-like symptoms (4.54%), impaired ability to concentrate (4.54%), blurred vision (4.54%), diarrhea (4.54%), lack of appetite (4.54%),
Part II:
Number of individual binge or urge events, as well as the number of days in which binge or urge events occurred were collected from patient diaries. Table 1: Tally of Binges and Urges to Binge presents the Number of binges, binge urges, mean number of binges per week, mean number of binge event days per week, mean number of binge urges per week and mean number of binge urge days per week. During the three phases there were a total of 135 binges and 71 urges in the two-week baseline phase, 199 binges and 295 urges in the 8-week treatment phase, and 64 binges and 27 urges in the two-week follow-up phase.
Participant reported that 66% of urges (196) were treated (some after beginning to binge) of which 81.1% (159) were treated with 60 mg, 16.3% (32) with 120 mg, and 2.6% (5) with 180 mg.
In 86% of treated urges (169 of 196), patients reported that treatment was helpful during the treatment phase.
Binges Table 1: Tally of Binges and Urges to Binge
Table 1: Tally of Binges and Urges to Binge
Link: Binges
Link: Urges
Number of binges, binge urges and mean number of binges per week, mean number of binge event days per week, mean number of binge urges per week and mean number of binge urge days per week, respectively
|
Total # binges
|
Total # urges
|
Number of Binges Per Week
Mean (±SD)
|
Difference from Baseline in # Binges Per Week
Range
(p-value)
|
Number of Binge Days Per Week
Mean (±SD)
|
Difference from Baseline in # Binge Days Per Week
Range
(p-value)
|
Number of Binge Urges Per Week
Mean (±SD)
|
Difference from Baseline in # Binge Urges Per Week
Range
(p-value)
|
Number of Binge Urge Days Per Week
Mean (±SD)
|
Difference from Baseline in # Binge Urge Days Per Week
Range
(p-value)
|
Baseline
Phase
|
135
|
71
|
4.9
(± 2.26)
|
|
4.1 (±1.49)
|
|
2.56 (±1.66)
|
|
2.12 (±1.33)
|
|
Treatment
Phase
|
199
|
295
|
1.58 (±2.23)
to
2.67 (±3.63)
|
-2.3
to
-3.4
(p-value 0.0005 - 0.0034)
|
1.32 (±2.03)
to
2.08 (±2.27)
|
-2.8
to
-2.0
(p-value 0.0005 – 0.005)
|
2.20 (±2.62)
to
4.67 (±3.37)
|
-0.4
to
2.11
(p-value 0.0176 – 1)
|
1.67 (±1.72)
to
3.25 (±2.01)
|
-0.2
to
1.13
(p-value 0.0420 – 0.6377)
|
Follow-up
Phase
|
64
|
27
|
2.67 (±3.09)
|
-2.3 (±2.35)
|
2.24 (±2.20)
|
-1.8 (±1.90)
|
1.15 (±1.41)
|
-1.4 (±1.41)
|
2.24 (±2.20)
|
-1.1 (±1.09)
|
Mean weekly number of binge events: Composite means are presented in Table 1. The mean number of binges per week during the baseline period was 4.9 (± 2.26). During the 8-week treatment period the number of binges per week decreased and ranged from 1.58 (± 2.23) to 2.67 (± 3.63). The mean number of binges during the two-week follow-up period was 2.67 (± 3.09).
Statistically significant differences from baseline period to treatment period were found at each treatment week, with the decrease in mean number of binges ranging from − 2.3 (± 1.89) to -3.4 (± 1.70) per week (p-values ranging from 0.0005 to 0.0034).
The overall mean number of binges per week for the treatment phase also differed significantly from baseline (p = 0.0005).
The mean number of binges per week in the follow-up phase was not statistically significantly different from treatment phase mean (p = 0.2881) but did differ significantly from the baseline phase (p = 0.0210).
Mean number of binge event days per week: The mean number of binge event days per week during the baseline phase was 4.08 (± 1.49). The mean number of binge event days per week during the treatment phase decreased and ranged from 1.38 to 2.08. The mean number of binge event days during the follow-up phase was 2.24 (± 2.20).
Statistically significant differences from baseline to treatment period were found at each week, with decrease in binges ranging from − 2 to -2.8 (p-values ranging from 0.0005 to 0.0049), Follow-up mean number of binge event days was not statistically significant different from treatment period (p = 0.2246).
Urges Table 1: Tally of Binges and Urges to Binge
Link: Binges
Link: Urges
Mean weekly number of urges: The mean number of urges per week during the baseline phase was 2.56 (± 1.66). Mean number of urges per week during the treatment phase ranged from 4.67 (± 3.37) to 2.20 (± 2.62). The difference between baseline and treatment phases was statistically insignificant (p = 0.8501).
The mean number of urges per week during the follow-up phase was 1.15 (± 1.41).
The mean number of urges per week during the follow-up phase differed significantly from the treatment (p = 0.0029) and from the baseline phases (p = 0.0034).
Mean number of urge event days per week: The mean number of urge event days per week during the baseline phase was 2.12 (± 1.33). The mean number of urge event days per week during the treatment phase ranged from 1.67(± 1.72) to 3.25(± 2.01). The mean number of urge event days per week during the follow-up phase was 0.98 (± 1.23)
When compared with the baseline phase, only the first week of follow-up demonstrated a statistically significant difference in number of urge event days per week (p = 0.0420).
When compared with the baseline phase, the overall follow-up period demonstrated no statistically significant difference in number of urge event days per week (p = 0.9697).
Like the mean number of urges per week, the follow-up phase had a statistically significant decrease in mean number of urge event days per week when compared with the treatment phase (p = 0.0059) but an insignificant change when compared with baseline phase (p = 0.9697).
Changes in variables between phases are presented visually in Fig. 2.
Changes over time of mean number of binges and urges per week are presented visually in Fig. 3.
Changes over time of mean number of binge and urge event days per week are presented visually in Fig. 4.
Patient Severity Of Illness And Post-treatment Condition Scoring:
Significances of Patient Severity of Illness and Post-treatment Condition Scoring, between weeks of treatment can be seen in Table 3.
Table 2
Changes in variables between phases. Statistically significant values (p < 0.05) appear in bold.
| Total # binges | Total # urges | Number of Binges Per Week Mean (± SD) | Difference from Baseline in # Binges Per Week Range (p-value) | Number of Binge Days Per Week Mean (± SD) | Difference from Baseline in # Binge Days Per Week Range (p-value) | Number of Binge Urges Per Week Mean (± SD) | Difference from Baseline in # Binge Urges Per Week Range (p-value) | Number of Binge Urge Days Per Week Mean (± SD) | Difference from Baseline in # Binge Urge Days Per Week Range (p-value) |
Baseline Phase | 135 | 71 | 4.9 (± 2.26) | | 4.1 (± 1.49) | | 2.56 (± 1.66) | | 2.12 (± 1.33) | |
Treatment Phase | 199 | 295 | 1.58 (± 2.23) to 2.67 (± 3.63) | -2.3 to -3.4 (p-value 0.0005–0.0034) | 1.32 (± 2.03) to 2.08 (± 2.27) | -2.8 to -2.0 (p-value 0.0005–0.005) | 2.20 (± 2.62) to 4.67 (± 3.37) | -0.4 to 2.11 (p-value 0.0176–1) | 1.67 (± 1.72) to 3.25 (± 2.01) | -0.2 to 1.13 (p-value 0.0420–0.6377) |
Follow-up Phase | 64 | 27 | 2.67 (± 3.09) | -2.3 (± 2.35) | 2.24 (± 2.20) | -1.8 (± 1.90) | 1.15 (± 1.41) | -1.4 (± 1.41) | 2.24 (± 2.20) | -1.1 (± 1.09) |
Table 3
Significances of Patient Severity of Illness and Post-treatment Condition Scoring, between weeks of treatment (Statistically sifnificant changes (p < 0.05) appear in bold).
Variable | Baseline vs. treatment periods | Follow-up vs. treatment periods | Follow-up vs. baseline periods |
Mean number of Binges per Week | p = 0.0005 | p = 0.2881 | p = 0.0212 |
Mean number of binges event days per week | p = 0.0005 | p = 0.2246 | p = 0.0098 |
Mean number of Urges per Week | p = 0.8501 | p = 0.0029 | p = 0.0034. |
Mean number of Urge event days per week | P = 0.9697 | p = 0.0059 | p = 0.9697 |
CGI-S: There was a statistically significant decrease during all 8 weeks of the treatment phase when compared with the baseline phase (p = 0.002- p = 0.0156).
YBOCS-BE: There was a statistically significant decrease during all 8 weeks of the treatment phase when compared with the baseline phase (p = 0.002- p = 0.0161).
Adverse events and side effects.
There were no adverse events reported during all 251 treatments in the treatment phase.
Safety monitoring revealed no deviation from baseline for all parameters: physical examination (including an ear, nose and throat (ENT) exam); vital signs (blood pressure, pulse rate, and temperature); blood laboratory tests (biochemistry and CBC), and urine toxicology (cannabinoids screen, benzodiazepine screen, amphetamine screen, methadone metabolite).
The following side effects were reported during the 8 weeks of treatment: headache (5.17%), sneezing (4.38%), tiredness (1.59%), and nausea (3.98%). Affected patients did not consider these as serious, no medical treatment was needed, and no alteration of treatment was needed as a result.
Patients reported a lingering bitter taste in the naso/oropharynx after administering treatment doses.