NOG112264

GlaxoSmithKline

980 Great West Road, Brentford, Middlesex, United Kingdom,

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

No

No

No

Final

22 May 2015

No

Yes

22 Jan 2015

No

The primary objective is to assess the effect of ozanezumab on the physical function and survival of Amyotrophic Lateral Sclerosis (ALS) subjects over a treatment period of 48 weeks. Function will be measured using the Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R).

The study was split into Part A (intensive safety monitoring for an initial subset of participants during the first four infusions of study drug) and Part B; recruitment was halted until an Independent Data Monitoring Committee (IDMC) reviewed Part A data. On the IDMC’s recommendation, recruitment into Part B commenced (less intensive safety monitoring required). The IDMC was deployed for the duration of the study to review unblinded safety and selected efficacy data at regular intervals throughout the study period. For participants randomized in Part A, the investigator sought agreement from the GSK study medical monitor prior to administering the next dose (until IDMC recommendation to start Part B). A GSK safety review team comprising the Safety Physician, Safety Scientist, Medical Monitor, and Statistician met at regular intervals throughout the study to review blinded safety information. The study was designed to allow for participants to provide key efficacy and safety data over the telephone should they not be able to attend clinic (with medical monitor approval).

20 Dec 2012

No

Yes

Australia: 14

Canada: 38

Japan: 13

Korea, Republic of: 27

United States: 29

Netherlands: 21

United Kingdom: 21

Belgium: 14

France: 39

Germany: 67

Italy: 20

303

182

0

0

0

0

0

0

235

68

0

Treatment Period (overall period)

Randomised - controlled

Yes

Placebo

Solution for injection/infusion

Intravenous use

Normal saline (0.9% sodium chloride) administered by intravenous infusion every 2 weeks up to Week 46 (last dose)

Ozanezumab

Solution for injection/infusion

Intravenous use

Ozanezumab 200 milligrams per milliliter (mg/mL) solution diluted at a dose of 15 milligrams per kilogram (mg/kg) and administered by intravenous infusion every 2 weeks up to Week 46 (last dose)

Placebo

Ozanezumab 15 mg/kg

Placebo

Ozanezumab 15 mg/kg

The joint rank score is a combined assessment of function and survival, whereby function is assessed using change from Baseline in the ALSFRS-R total score. To calculate the joint rank scores, every participant was compared with all other participants in a pair wise manner and assigned a score of -1, 0 or 1 based on their relative outcomes. The joint rank score for a subject is then the sum of their scores across the pair wise comparisons. Outcomes are considered in a hierarchical manner with death considered a worse outcome than functional decline, and a large functional decline considered a worse outcome than a small/no functional decline. See the description of the subsequent outcome measure for information regarding the ALSFRS-R questionnaire. The Intent-to-Treat (ITT) population was comprised of all randomized participants who received at least one dose of investigational product.

Primary

Week 48

Placebo v Ozanezumab 15 mg/kg

303

Pre-specified

-30

2-sided

The ALSFRS-R is a questionnaire-based rating scale that assesses the functioning of ALS participants across four domains: gross motor activity, fine motor activity, bulbar function, and respiratory function. The ALSFRS-R consists of 12 questions, each of which is scored on a 5-point scale from 0 to 4, where 4 is the best possible outcome and 0 is the worst. The total score is calculated by summing the responses to each of the 12 individual questions. The maximum total score is therefore 48; lower scores indicate worse functioning. If there were any missing responses to questions, the total score was set to missing. The Week 0 (Visit 2) value was considered to be the Baseline value. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. A mixed-model repeated measures adjusted for treatment, visit, treatment by visit, Baseline ALSFRS-R, Baseline ALSFRS-R by visit, riluzole use, and country group was used for the analysis.

Secondary

Baseline and Week 48

Placebo v Ozanezumab 15 mg/kg

205

Pre-specified

-1.3

2-sided

The rate of decline was estimated by the change from Baseline in ALSFRS-R. The monthly slope for the ALSFRS-R score (i.e., the monthly rate of decline) was calculated as change from Baseline in the ALSFRS-R score at the last visit for that treatment period divided by the study day at the last visit for that treatment period /30.4. The Week 0 (Visit 2) value was considered to be the Baseline value. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. A random coefficients model with treatment, time, treatment by time, Baseline ALSFRS-R, Baseline ALSFRS-R by time, riluzole use, and country group in the model as fixed effects was used for the analysis. Time and intercept were included in the model as random effects.

Secondary

Baseline to Week 48

Placebo v Ozanezumab 15 mg/kg

299

Pre-specified

-0.12

2-sided

SVC was measured by using a validated spirometer. Three SVC measurements were performed for each participant at each assessment provided the difference from the second trial (if arranged by the numerical value) was not greater than 10%. If the difference between the best and the next best (based on the largest numerical value) SVC value from the first three trials was greater than 10%, additional trials (up to 5 in total) could have been performed. The Week 0 (visit 2) value was considered to be the Baseline value. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. A mixed-model repeated measures (MMRM) adjusted for treatment, visit, treatment by visit, Baseline SVC, Baseline SVC by visit, riluzole use. and country group was used for the analysis.

Secondary

Baseline and Week 48

Placebo v Ozanezumab 15 mg/kg

194

Pre-specified

-0.127

2-sided

The HHD is a device placed between the hand of the practitioner and the tested body part and provides a quantified measurement of muscle strength. Each muscle was tested twice, and both values were recorded. Additionally, a third trial could have been performed if the variability between the first two trials was greater than 15 % or if the rater thought that one of the first two trials was not valid. The Week 0 (Visit 2) value was considered to be the Baseline value. Percent change from Baseline for each muscle group was calculated as 100*(HHD score minus the Baseline score) divided by the Baseline score. The average percent change was the mean percent change across the muscle groups that were non-missing/non-zero at Baseline. MMRM adjusted for treatment, visit, treatment by visit, number of non-missing/non-zero muscle groups at Baseline, number of non-missing/non-zero muscle groups at Baseline by Visit, riluzole use, and country group was used for the analysis.

Secondary

Baseline and Week 48

Placebo v Ozanezumab 15 mg/kg

194

Pre-specified

-8.2

2-sided

The CGI-I scale is a single observer-rated item measuring global improvement relative to Baseline. The CGI-I score is rated on a 7-point scale, from 1 (very much improved) to 7 (very much worse). Participant status at Baseline was assessed using the Clinical Global Impression Severity scale (CGI-S), which is a 7-point scale (1: normal, not at all ill; 7: most extremely ill) used to rate the severity of the participant's illness. Participants achieving a score of 1-4 in the CGI-I at Week 48 were considered to be responders. A a logistic regression adjusted for CGI-S at Baseline, riluzole use, and world region was used for the analysis.

Secondary

Week 48

Placebo v Ozanezumab 15 mg/kg

198

Pre-specified

0.73

2-sided

Overall survival is defined as the time from randomization to death or censoring at the time point of analysis, whichever comes first. Kaplan Meier estimates at Week 48 were evaluated at Day 344. A participant was considered to have completed if he/she was censored at Day 344. Kaplan Meier estimates at Week 60 were evaluated at Day 428. A participant was considered to have completed if he/she was censored at Day 428. Confidence intervals were estimated using the Brookmeyer Crowley method. Results are shown as the estimated percentage of participants alive at Weeks 48 and 60. Week 48: Only on-treatment data (data within 21 days of the last dose) were analyzed. Week 60: Including off treatment data (data after 21 days after the last dose) were analyzed.

Secondary

Week 48 and Week 60

Week 48

Placebo v Ozanezumab 15 mg/kg

303

Pre-specified

0.99

2-sided

Week 60

Placebo v Ozanezumab 15 mg/kg

303

Pre-specified

1.03

2-sided

Progression-free survival at Week 48 is defined as the time from randomization to progression (decline of at least six points on the ALSFRS-R from Baseline) or death or censored at Week 48, whichever comes first. Kaplan Meier estimates at Week 48 were evaluated at Day 344. A participant was considered to have completed if he/she was censored at Day 344. Confidence intervals were estimated using the Brookmeyer Crowley method. Results are shown as the estimated percentage of participants alive and without disease progression at Week 48.

Secondary

Week 48

Placebo v Ozanezumab 15 mg/kg

303

Pre-specified

1.07

2-sided

The EQ-5D is a standardized measure of health status developed by the EuroQol group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L Qol comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each of these dimensions, the participant self assigned a score: 1 (no problems); 2 (slight problems); 3 (moderate problems); 4 (severe problems); 5 (extreme problems). A utility score for each participant was calculated based on the value set for England. The Week 0 (Visit 2) value was considered to be the Baseline value. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. A mixed-model repeated measures adjusted for treatment, visit, treatment by visit, Baseline EQ5D, Baseline EQ5D by visit, riluzole use, and country group was used for the analysis.

Secondary

Baseline and Week 48

Ozanezumab 15 mg/kg v Placebo

205

Pre-specified

-0.004

2-sided

The ALSAQ-40 is a disease specific health status assessment for individuals with ALS/motor neurone disease. The ALSAQ-40 is comprised of 40 questions measuring 5discrete dimensions of health status that are affected by the disease: physical mobility (10 items); activities of daily living and independence (10 items); eating and drinking (3 items); communication (7 items); emotional reactions (10 items). Participants were asked to indicate the frequency of each event by selecting one of five options (Likert scale: 0-4): never/rarely/sometimes/often/ always or cannot do at all. The total score (maximum possible score=160) was calculated by adding the five domain scores. A low score indicates a better health state. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. A mixed-model repeated measures adjusted for treatment, Visit, Treatment by Visit, and Baseline ALSAQ-40 total score was used for the analysis.

Secondary

Baseline and Week 48

Placebo v Ozanezumab 15 mg/kg

198

Pre-specified

1.4

2-sided

On-treatment serious adverse events (SAE) and non-serious AEs were collected from the date of the first dose of study medication up to 21 days after the last dose of investigational product.

AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.

16.1

Placebo

Ozanezumab 15 mg/kg