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

Primary Purpose

Amyotrophic Lateral Sclerosis

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Ozanezumab

Placebo

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring Amyotrophic lateral sclerosis, efficacy, ozanezumab, safety

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ozanezumab IV

Placebo

Arm Description

Administered by IV route. Treatment period - 48 Weeks

Normal saline by IV route. Treatment period - 48 weeks

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT01753076

First Posted

December 17, 2012

Last Updated

November 27, 2017

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT01753076

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2017

Overall Recruitment Status

Completed

Study Start Date

December 20, 2012 (Actual)

Primary Completion Date

January 22, 2015 (Actual)

Study Completion Date

January 22, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Amyotrophic Lateral Sclerosis

Keywords

Amyotrophic lateral sclerosis, efficacy, ozanezumab, safety

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

304 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ozanezumab IV

Arm Type

Experimental

Arm Description

Administered by IV route. Treatment period - 48 Weeks

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Normal saline by IV route. Treatment period - 48 weeks

Intervention Type

Drug

Intervention Name(s)

Ozanezumab

Intervention Description

Ozanezumab injection solution

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Normal saline (0.9% sodium chloride) infusion

Primary Outcome Measure Information:

Title

Joint Rank Scores for Combined Analysis of Function (Amyotrophic Lateral Sclerosis Functional Rating Scale Revised [ALSFRS-R] Score) and 48 Week Overall Survival

Description

Time Frame

Week 48

Secondary Outcome Measure Information:

Title

Change From Baseline in the ALSFRS-R Total Score at Week 48

Description

Time Frame

Baseline and Week 48

Title

Rate of Decline Over Week 48 in the ALSFRS-R Total Score

Description

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.

Time Frame

Baseline to Week 48

Title

Change From Baseline in Slow Vital Capacity (SVC) at Week 48

Description

Time Frame

Baseline and Week 48

Title

Change From Baseline in Muscle Strength as Measured by Hand Held Dynamometry (HHD) Score at Week 48

Description

Time Frame

Baseline and Week 48

Title

Number of Clinical Global Impression-improvement Scale (CGI-I) Responders at Week 48

Description

Time Frame

Week 48

Title

Overall Survival at Week 48 and Week 60

Description

Time Frame

Week 48 and Week 60

Title

Progression-free Survival at Week 48

Description

Time Frame

Week 48

Title

Change From Baseline in the EuroQol 5 Dimensions-5 Level Short Form (EQ-5D-5L) Utility Score at Week 48

Description

Time Frame

Baseline and Week 48

Title

Change From Baseline in the Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) Total Score at Week 48

Description

Time Frame

Baseline and Week 48

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

GSK Investigational Site

City

Grand Rapids

State/Province

Michigan

ZIP/Postal Code

49503

Country

United States

Facility Name

GSK Investigational Site

City

Syracuse

State/Province

New York

ZIP/Postal Code

13210

Country

United States

Facility Name

GSK Investigational Site

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

Facility Name

GSK Investigational Site

City

Randwick

State/Province

New South Wales

ZIP/Postal Code

2031

Country

Australia

Facility Name

GSK Investigational Site

City

Herston

State/Province

Queensland

ZIP/Postal Code

4029

Country

Australia

Facility Name

GSK Investigational Site

City

Leuven

ZIP/Postal Code

3000

Country

Belgium

Facility Name

GSK Investigational Site

City

Calgary

State/Province

Alberta

ZIP/Postal Code

T3M 1M4

Country

Canada

Facility Name

GSK Investigational Site

City

London

State/Province

Ontario

ZIP/Postal Code

N6A 5A5

Country

Canada

Facility Name

GSK Investigational Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M4N 3M5

Country

Canada

Facility Name

GSK Investigational Site

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H2L 4M1

Country

Canada

Facility Name

GSK Investigational Site

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H3A 2B4

Country

Canada

Facility Name

GSK Investigational Site

City

Lille cedex

ZIP/Postal Code

59037

Country

France

Facility Name

GSK Investigational Site

City

Limoges cedex

ZIP/Postal Code

87042

Country

France

Facility Name

GSK Investigational Site

City

Montpellier cedex 5

ZIP/Postal Code

34295

Country

France

Facility Name

GSK Investigational Site

City

Nice cedex 3

ZIP/Postal Code

06202

Country

France

Facility Name

GSK Investigational Site

City

Paris cedex 13

ZIP/Postal Code

75651

Country

France

Facility Name

GSK Investigational Site

City

Ulm

State/Province

Baden-Wuerttemberg

ZIP/Postal Code

89081

Country

Germany

Facility Name

GSK Investigational Site

City

Muenchen

State/Province

Bayern

ZIP/Postal Code

81675

Country

Germany

Facility Name

GSK Investigational Site

City

Hannover

State/Province

Niedersachsen

ZIP/Postal Code

30625

Country

Germany

Facility Name

GSK Investigational Site

City

Bochum

State/Province

Nordrhein-Westfalen

ZIP/Postal Code

44789

Country

Germany

Facility Name

GSK Investigational Site

City

Jena

State/Province

Thueringen

ZIP/Postal Code

07747

Country

Germany

Facility Name

GSK Investigational Site

City

Berlin

ZIP/Postal Code

13353

Country

Germany

Facility Name

GSK Investigational Site

City

Torino

State/Province

Piemonte

ZIP/Postal Code

10126

Country

Italy

Facility Name

GSK Investigational Site

City

Verona

State/Province

Veneto

ZIP/Postal Code

37134

Country

Italy

Facility Name

GSK Investigational Site

City

Kanagawa

ZIP/Postal Code

252-0380

Country

Japan

Facility Name

GSK Investigational Site

City

Miyagi

ZIP/Postal Code

980-8574

Country

Japan

Facility Name

GSK Investigational Site

City

Osaka

ZIP/Postal Code

560-8552

Country

Japan

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

110-744

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

133-792

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

136-705

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Utrecht

ZIP/Postal Code

3584 CX

Country

Netherlands

Facility Name

GSK Investigational Site

City

Preston

State/Province

Lancashire

ZIP/Postal Code

PR2 9HT

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Brighton

ZIP/Postal Code

BN2 5BE

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Edgbaston,

ZIP/Postal Code

B15 2TT

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

28139349

Citation

Meininger V, Genge A, van den Berg LH, Robberecht W, Ludolph A, Chio A, Kim SH, Leigh PN, Kiernan MC, Shefner JM, Desnuelle C, Morrison KE, Petri S, Boswell D, Temple J, Mohindra R, Davies M, Bullman J, Rees P, Lavrov A; NOG112264 Study Group. Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017 Mar;16(3):208-216. doi: 10.1016/S1474-4422(16)30399-4. Epub 2017 Jan 28.

Results Reference

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

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

Amyotrophic Lateral Sclerosis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial