14 CLINICAL STUDIES

The efficacy of TOSYMRA is based on the relative bioavailability of TOSYMRA nasal spray compared to sumatriptan subcutaneous injection (4 mg) in healthy adults [see Clinical Pharmacology (12.3)] .

In controlled clinical trials enrolling more than 1,000 patients during migraine attacks who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 3, onset of relief began as early as 10 minutes following a 6 mg sumatriptan injection. Lower doses of sumatriptan injection may also prove effective, although the proportion of patients obtaining adequate relief was decreased and the latency to that relief is greater with lower doses.

In Study 1, 6 different doses of sumatriptan injection (n = 30 each group) were compared with placebo (n = 62) in a single-attack, parallel-group design; the dose-response relationship was found to be as shown in Table 2.

Table 2: Proportion of Patients with Migraine Relief and Incidence of Adverse Reactions by Time and by Sumatriptan Dose in Study 1
Dose of sumatriptan Injection	Percent Patients with Relief *				Adverse Reactions Incidence (%)
Dose of sumatriptan Injection	at 10 Minutes	at 30 Minutes	at 1 Hour	at 2 Hours	Adverse Reactions Incidence (%)
* Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication. † Efficacy of Tosymra nasal spray was demonstrated based on bioavailability to 4 mg sumatriptan SC injection.
Placebo	5	15	24	21	55
1 mg	10	40	43	40	63
2 mg	7	23	57	43	63
3 mg	17	47	57	60	77
4 mg †	13	37	50	57	80
6 mg	10	63	73	70	83
8 mg	23	57	80	83	93

In 2 randomized, placebo-controlled clinical trials of sumatriptan injection 6 mg in 1,104 patients with moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 10 minutes. Headache relief, as defined by a reduction in pain from severe or moderately severe to mild or no headache, was achieved in 70% of the patients within 1 hour of a single 6 mg subcutaneous dose of sumatriptan injection. Approximately 82% and 65% of patients treated with sumatriptan 6 mg had headache relief and were pain free within 2 hours, respectively.

Table 3 shows the 1- and 2-hour efficacy results for sumatriptan injection 6 mg in Studies 2 and 3.

Table 3: Proportion of Patients with Pain Relief and Relief of Migraine Symptoms after 1 and 2 Hours of Treatment in Studies 2 and 3
* P<0.05 versus placebo. † A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. ‡ Includes patients that may have received an additional placebo injection 1 hour after the initial injection. § Includes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection.
1-Hour Data	Study 2		Study 3
1-Hour Data	Placebo (n = 190)	Sumatriptan Injection 6 mg (n = 384)	Placebo (n = 180)	Sumatriptan Injection 6 mg (n = 350)
Patients with pain relief (Grade 0/1)	18%	70% *	26%	70% *
Patients with no pain	5%	48% *	13%	49% *
Patients without nausea	48%	73% *	50%	73% *
Patients without photophobia	23%	56% *	25%	58% *
Patients with little or no clinical disability †	34%	76% *	34%	76% *
2-Hour Data	Study 2		Study 3
2-Hour Data	Placebo ‡	Sumatriptan Injection 6 mg §	Placebo ‡	Sumatriptan Injection 6 mg §
Patients with pain relief (Grade 0/1)	31%	81% *	39%	82% *
Patients with no pain	11%	63% *	19%	65% *
Patients without nausea	56%	82% *	63%	81% *
Patients without photophobia	31%	72% *	35%	71% *
Patients with little or no clinical disability †	42%	85% *	49%	84% *

Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks.

The efficacy of sumatriptan injection was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the patient, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers).