Study of Ozanezumab (GSK1223249) Versus Placebo in the Treatment of Amyotrophic Lateral Sclerosis

Study Overview
=================
Brief Summary
-----------------
This is a 48-week, randomised, multi-centre, double-blind, placebo-controlled, parallel group investigation of the efficacy and safety of intravenous (IV) ozanezumab (GSK1223249) compared to placebo in subjects with Amyotrophic Lateral Sclerosis (ALS). Following a screening period of up to four weeks, eligible subjects will be randomised (1:1) to receive IV placebo or 15 milligram (mg)/ kilogram (kg) IV ozanezumab every 2 weeks for a period of 48 weeks with a follow-up visit around 14 weeks after the last infusion. A total of approximately 294 eligible subjects will be randomised from approximately 37 centers worldwide. The primary objective is to assess the effect of ozanezumab on the physical function and survival of ALS subjects over a treatment period of 48 weeks. Function will be measured using the ALS Functional Rating Scale - Revised (ALSFRS-R). Secondary objectives include the evaluation of other clinical outcomes associated with ALS (respiratory function, muscle strength, progression free survival and overall survival) in support of the primary objective. Quality of life, safety, tolerability, immunogenicity and pharmacokinetics (ozanezumab and riluzole) will also be assessed.

Official Title
-----------------
Study NOG112264, a Phase II Study of Ozanezumab (GSK1223249) Versus Placebo in the Treatment of Amyotrophic Lateral Sclerosis

Conditions
-----------------
Amyotrophic Lateral Sclerosis

Intervention / Treatment
-----------------
* Drug: Ozanezumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with diagnosis of familial or sporadic ALS Onset of muscle weakness no more than 30 months before screening visit. Slow Vital Capacity (SVC) of at least 65% predicted for gender, age, ethnicity and height at Screening. If on riluzole, the dose must have been stable for at least 28 days prior to Baseline visit. Age 18 - 80 years inclusive. Female subjects may participate if they are of non-child-bearing potential or if they are of child-bearing potential they must agree to use the approved contraceptive methods Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2x upper limit of normal (ULN); alkaline phosphatase and bilirubin <=1.5xULN. QTc (both QTcB and QTcF) <450 milliseconds (msec) or <480 msec for subjects with Bundle Branch Block at Screening and Baseline (average from triplicate ECGs). Exclusion Criteria: Patients with other neuromuscular disorders (including a history of polio) which in the opinion of the investigator could have contributed to the muscular atrophy or weakness caused by ALS Patients with primary lateral sclerosis, monomelic ALS, ALS Parkinsonism dementia complex. Patients requiring non-invasive or mechanical ventilation (non-invasive ventilation for sleep apnoea is allowed subject to discussion with Medical Monitor) Patients on diaphragmatic pacing. Presence of any of the following clinical conditions: Drug abuse or alcoholism, uncontrolled hypertension, active major infectious disease, unstable psychiatric illness within 90 days of the Screening visit Subjects, who in the investigator's judgement, pose a significant suicide risk. - Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), positive Hepatitis B surface antigen or Hepatitis C antibody test. Subjects who have participated in a clinical trial involving receipt of a biopharmaceutical product within 6 months prior to the first dosing day. Exposure to non-biological experimental agents 1 month or 5 half-lives prior to Baseline visit (whichever is longer). History of sensitivity to ozanezumab, or components thereof, or a history of other allergies that, in the opinion of the investigator, contraindicates participation in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ozanezumab IV<br>Administered by IV route. Treatment period - 48 Weeks | Drug: Ozanezumab<br>* Ozanezumab injection solution<br>|
| Placebo Comparator: Placebo<br>Normal saline by IV route. Treatment period - 48 weeks | Drug: Placebo<br>* Normal saline (0.9% sodium chloride) infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Joint Rank Scores for Combined Analysis of Function (Amyotrophic Lateral Sclerosis Functional Rating Scale Revised [ALSFRS-R] Score) and 48 Week Overall Survival | The joint rank score is a combined assessment of function and survival. Function is assessed using change from Baseline in the ALSFRS-R total score. To calculate 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. A subject's joint rank score is the sum of their scores across the pair wise comparisons. The . The ALSFRS-R was a quickly administered (5 min) ordinal rating scale used to determine a participant's assessment of their capability and independence in 12 functional activities. There were 12 questions, graded by the participant 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing. Lower scores of ALSFRS-R reflect greater impairment. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the ALSFRS-R Total Score at Week 48 | 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. The ALSFRS-R was a quickly administered (5 min) ordinal rating scale used to determine a participant's assessment of their capability and independence in 12 functional activities. There were 12 questions, graded by the participant 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing. | Baseline and Week 48 | 
| Rate of Decline Over Week 48 in the ALSFRS-R Total Score | 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 devided by 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. The ALSFRS-R was a quickly administered (5 min) ordinal rating scale used to determine a participant's assessment of their capability and independence in 12 functional activities. There were 12 questions, graded by the participant 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing. | Baseline to Week 48 | 
| Change From Baseline in Slow Vital Capacity (SVC) at Week 48 | 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. | Baseline and Week 48 | 
| Change From Baseline in Muscle Strength as Measured by Hand Held Dynamometry (HHD) Score at Week 48 | 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. | Baseline and Week 48 | 
| Number of Clinical Global Impression-improvement Scale (CGI-I) Responders at Week 48 | 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. | Week 48 | 
| Overall Survival at Week 48 and Week 60 | 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. | Week 48 and Week 60 | 
| Progression-free Survival at Week 48 | 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. | Week 48 | 
| Change From Baseline in the EuroQol 5 Dimensions-5 Level Short Form (EQ-5D-5L) Utility Score at Week 48 | 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. EQ-5D-5L is a standardized, participant-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-Visual Analog Scale (EQ-VAS). The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 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).Minimum score on scale was 1 and maximum score was 5 for each dimension. A negative change from Baseline indicates improvement. | Baseline and Week 48 | 
| Change From Baseline in the Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) Total Score at Week 48 | The ALSAQ-40 is a disease specific health status assessment for individuals with ALS/motor neuron 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 (minimum possible score=0, 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. | Baseline and Week 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Amyotrophic lateral sclerosis, efficacy, ozanezumab, safety