Betaseron

Clinical Pharmacology

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Clinical Pharmacology

Betaseron

The clinical effects of Betaseron were studied in four randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis.

The effectiveness of Betaseron in relapsing-remitting MS (Study 1) was evaluated in a double blind, multiclinic, randomized, parallel, placebo controlled clinical investigation of two years duration. The study enrolled MS patients, aged 18 to 50, who were ambulatory (EDSS of < 5.5), exhibited a relapsing-remitting clinical course, met Poser's criteria¹for clinically definite and/or laboratory supported definite MS and had experienced at least two exacerbations over two years preceding the trial without exacerbation in the preceding month. Patients who had received prior immuno-suppressant therapy were excluded.

An exacerbation was defined as the appearance of a new clinical sign/symptom or the clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persisted for a minimum of 24 hours.

Patients selected for study were randomized to treatment with either placebo (N=123), 0.05 mg of Betaseron (N=125), or 0.25 mg of Betaseron (N=124) self-administered subcutaneously every other day. Outcome based on the 372 randomized patients was evaluated after two years.

Patients who required more than three 28-day courses of corticosteroids were removed from the study. Minor analgesics (acetaminophen, codeine), antidepressants, and oral baclofen were allowed ad libitum, but chronic nonsteroidal anti-inflammatory drug (NSAID) use was not allowed.

The primary protocol-defined outcome measures were 1) frequency of exacerbations per patient and 2) proportion of exacerbation free patients. A number of secondary clinical and magnetic resonance imaging (MRI) measures were also employed. All patients underwent annual T2 MRI imaging and a subset of 52 patients at one site had MRIs performed every six weeks for assessment of new or expanding lesions.

The study results are shown in Table 1.

TABLE 1: Two Year RRMS Study Results Primary and Secondary Clinical Outcomes

Efficacy Parameters		Treatment Groups			Statistical Comparisons p-value
Primary End Points		Placebo (N=123)	0.05 mg (N=125)	0.25 mg (N=124)	Placebo vs 0.05 mg	0.05 mg vs 0.25 mg	Placebo vs 0.25 mg
Annual exacerbation rate		1.31	1.14	0.90	0.005	0.113	0.0001
Proportion of exacerbation-free patients†		16%	18%	25%	0.609	0.288	0.094
Exacerbation	0†	20	22	29	0.151	0.077	0.001
frequency	1	32	31	39
per patient	2	20	28	17
	3	15	15	14
	4	15	7	9
	> 5	21	16	8
Secondary Endpoints† †
Median number of months to first on-study exacerbation		5	6	9	0.299	0.097	0.010
Rate of moderate or severe exacer-bations per year		0.47	0.29	0.23	0.020	0.257	0.001
Mean number of moderate or severe exacerbation days per patient		44.1	33.2	19.5	0.229	0.064	0.001
Mean change in EDSS score‡ at endpoint		0.21	0.21	-0.07	0.995	0.108	0.144
Mean change in Scripps score‡‡ at endpoint		-0.53	-0.50	0.66	0.641	0.051	0.126
Median duration in days per exacerbation		36	33	35.5	ND	ND	ND
% change in mean MRI lesion area at endpoint		21.4%	9.8%	-0.9%	0.015	0.019	0.0001
ND Not done † 14 exacerbation free patients (0 from placebo, six from 0.05 mg, and eight from 0.25 mg) dropped out of the study before completing six months of therapy. These patients are excluded from this analysis. † † Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individually but are included as a function of the EDSS. ‡ EDSS scores range from 1-10, with higher scores reflecting greater disability ‡‡ Scripps neurologic rating scores range from 0-100, with smaller scores reflecting greater disability.