Synopsis of Study Results
Name ofDaiichi Sankyo Company, Limited

Sponsor/Company
Name of Finished ProductGabalon Intrathecal Injection(if approved)
Name of Active Ingredientbaclofen

Title of Study• Phase 3 Clinical Study of DL-404 (Baclofen Injection) Intrathecally
Administered with MDT-3101 (implantable pump system) (long-term safetystudy)• Postmarketing Clinical Study of Baclofen Injection Administered with
Implantable Pump System (extension study of clinical study)

Investigators-Study centers

10 medical institutions

Publications (of studyNot publishedresults)
Studied period

Start date: August 23, 2002, the day after the day of final observations of thefirst patient in the preceding long-term maintenance treatment
study (Japic CTI-050061)
End date: January 26, 2007 (date of regulatory approval)
Postmarketing clinical study: Only adult patients, April 12, 2005 (day after
date of regulatory approval for adults) to April 30, 2006

Phase of development

Phase 3 (extention to phase 4)

Objectives

Therapeutic

Methodology

Multicenter, open-label study

Number of Patients

Planned: 13(planned and analyzed)

Analyzed: 24Diagnosis and main

Disease:criteria for inclusion

Severe spastic paralysis of spinal origin
Spastic paralysis associated with spinal cord injury, multiple sclerosis,
spinocerebellar degeneration (hereditary spastic paraplegia), spinal vasculardisorder, ossification of posterior longitudinal ligament, or cervicalspondylosis
Severe spastic paralysis of cerebral origin
Spastic paralysis associated with spastic cerebral palsy or head trauma
Inclusion criteria:
Male and female hospitalized patients and outpatients satisfying all of thefollowing conditions will be included:
1） Responders as of the conclusion of the preceding long-term maintenancetreatment study (Japic CTI-050061) found to pose no safety problems by
the investigator or subinvestigator2） Available for periodic follow-up during study period
Exclusion criteria:
None

Test product, dose andThe following 2 drug products were used as the investigational products:

mode of administration,(1) DL-404 for injection, 5 mL ampoule (2 mg/mL), batch no. M01014-2Aand batch number(2) DL-404 for injection, 20 mL ampoule (0.5 mg/mL), batch no. M01014-4A
The patients continued to use the investigational device used in the preceding
long-term maintenance treatment study (Japic CTI-050061). A device fromamong the following was selected if replacement was required:(3) 18 mL pump reservoir, model no. 8627L18(4) 10 mL pump reservoir, model no. 8627L10(5) One-piece catheter, model no. 8709
(6) Two-piece catheter, model no. 8711
(7) Programmer, model no. 8821
(8) Tunneling accessory, model nos. 8590-41, 859138, 859160

Doses and modes of administration:
The initial dose in the study was the dose used at the conclusion of thepreceding long-term maintenance treatment study (Japic CTI-050061). A dose
increase was allowed once every 24 hours within the range of 40% of theimmediately preceding dose of the investigational product for disease ofspinal origin or 20% for disease of cerebral origin (including that in pediatricpatients) as appropriate when dose adjustment for maintenance of efficacy wasrequired.
The upper limits for the daily dose were 1500 µg/day for disease of spinal
origin, 1000 µg/day for disease of cerebral origin, and 800 µg/day forpediatric patients (16 years of age or younger).
When required, dose reduction of the daily dose was allowed within therange of 20% of the immediately preceding dose.

Duration of treatment

Until regulatory approval of DL-404 and MDT-3101 for the respective
diseases

Reference therapy, doseand mode of

administration, and batch
numberEndpoints

Efficacy endpoints(1) Mean Ashworth score of 8 left and right lower extremity sites(2) Mean Ashworth score of 8 left and right upper extremity sites (onlypatients with severe spastic paralysis of cerebral origin)(3) Spasm score (except in patients with spastic cerebral palsy)(4) Kenny self-care score
Safety endpoints(1) Adverse events(2) Adverse drug reactions to investigational product (i.e., adverse events forwhich causal relationship with investigational product was not ruled out)(3) Device-related problems (i.e., problems for which causal relationship withinvestigational device was not ruled out)(4) Concurrent events (i.e., events for which causal relationship with surgery,procedure, or refilling technique was not ruled out)(5) Vital signs and laboratory test results

Statistical methods(1) Analysis populations
All subjects without significant GCP noncompliance were included in theanalyses.
(2) Statistical methods for efficacy endpoints
Pre- and post-treatment differences were determined for the Ashworth
scores, Spasm scores, and Kenny self-care scores of each patient. Changes inmean Ashworth scores were calculated along with the 95% confidenceintervals.
(3) Statistical methods for safety endpoints
Tables were prepared and incidences were calculated for the patients whosuffered an adverse event, the patients who suffered an adverse drug reaction
to the investigational product, the patients who suffered a device-relatedproblem, the patients who suffered a concurrent event, and the patients whosuffered an abnormal change.

Summary – Conclusions

Efficacy Results
All 24 patients enrolled (19 adults and 5 children) were included in theanalysis population.
After the preceding long-term maintenance treatment study (JapicCTI-050061), the change (and 95% confidence internal) in mean Ashworth
score for the 8 left and right lower extremity sites was 1.72 to 2.24 (1.24,

2.51), which was a significant decrease indicating the anti-spasticity effect of
DL-404 until 48 months.
After the preceding long-term maintenance treatment study (JapicCTI-050061), the change (and 95% confidence interval) in mean Ashworth
score for the 8 left and right upper extremity sites was 0.65 to 1.20 (0.06,2.34), which was a significant decrease indicating the anti-spasticity effect of
DL-404 until 45 months.
After the preceding long-term maintenance treatment study (JapicCTI-050061), the change (and 95% confidence interval) in mean left and rightspasm score was 1.33 to 1.76 (0.21, 2.62), which was a significant decreaseindicating the anti-spasticity effect of DL-404 until 48 months.
An assessment of patient independence according to Kenny self-care totals
revealed no improvement.
Safety Results
Twenty-four of the 24 patients experienced 556 adverse events for anadverse event incidence of 100.0%. Although no deaths were reported, 8 of
the patients suffered 14 other serious adverse events (including those in thepostmarketing clinical study).
Thirty-seven adverse events for which a causal relationship with theinvestigational product was not ruled out (adverse drug reactions) werereported in 13 of the 24 patients for an adverse drug reaction incidence of54.2%. The adverse drug reactions were malaise, constipation, headache,pruritus, vomiting, increased blood CK, hypesthesia, peripheral coldness,
nausea, dysuria, urinary retention, extrasystoles, asthenia, chest discomfort,pain, device-related discomfort, increased prostatic specific antigen, muscular
weakness, urinary incontinence, epididymitis, prostatitis, and rash. The
incidences of adverse drug reactions classified by underlying disease were73.3% (35 occurrences in 11 of 15 patients) for disease of spinal origin(adults) and 50.0% (2 occurrences in 2 of 4 patients) for disease of cerebral
origin (adults). No adverse drug reaction was reported for disease of cerebralorigin (children).
Eleven adverse events for which a causal relationship with theinvestigational device was not ruled out (device-related problems) werereported in 8 of the 24 patients for a device-related problem incidence of33.3%. The problems reported were wound complication, implant site
reaction, extrasystoles, pain, device-related discomfort, increased blood CK,
hypesthesia, and rash.
Seven adverse events for which a causal relationship with surgery, aprocedure, or refill technique was not ruled out (concurrent events) werereported in 5 of the 24 patients for a concurrent event incidence of 20.8%. The
concurrent events reported were device-related complication, device-related
discomfort, wound complication, hypesthesia, and rash.
For overall treatment (following pump implantation), with the preceding
long-term maintenance treatment study and postmarketing clinical study
combined, adverse event incidence was 100.0% (949 occurrences in 25 of 25patients), adverse drug reaction incidence was 76.0% (73 events in 19 of 25patients), device-related problem incidence was 52.0% (25 occurrences in 13of 25 patients), and concurrent event occurrence was 32.0% (14 occurrencesin 8 of 25 patients).
Conclusions
The study demonstrated a long-term anti-spasticity effect was maintained
following the preceding long-term maintenance treatment study (JapicCTI-050061).
None of the patients (24) enrolled in the study (and postmarketing clinicalstudy) suffered any problematic severe adverse drug reaction. No adverse drug
reaction was reported in the pediatric patients. No adverse drug reactions
attributable to overdose or underdose were reported. The study showed that
long-term safety was maintained following the previously conductedlong-term maintenance treatment study (Japic CTI-050061).
The daily dose beginning 6 months after pump implantation (including thatin the postmarketing clinical study) was on average adjusted over a range of
172.61 to 271.30 μg/day. This range classified by the underlying disease wason average 205.44 to 295.16 μg/day for disease of spinal origin (adults), 94.16
to 140.06 μg/day for disease of cerebral origin (adults), and 98.56 to 198.65
μg/day for disease of cerebral origin (children).

Date of the synopsis

2011 / 07 / 30