Trial Outcomes & Findings for Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe) (NCT NCT01212094)

NCT ID: NCT01212094

Last Updated: 2016-03-28

Results Overview

This outcome is for interim analysis of the efficacy of B cell depletion from the CSF 3 months after giving rituximab or placebo into the cerebrospinal fluid (CSF). It compares concentration of chemokine CXCL13 before and 3 months after administration of drug into the CSF. We averaged two time-points before treatment (CSF collected 1 year apart, at month -12 and month 0) and compared it to the single time-point (month 3), which was 3 months from the initiation of drug dosing. CXCL13 is released by activated B cells, T cells and by follicular dendritic cells and has been linked previously with MS inflammation in the brain and spinal cord. The protocol-stipulated threshold for trial continuation was at least 25% decrease in CSF CXCL13 induced by active treatment with significance level p=0.025.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

44 participants

Primary outcome timeframe

3 months

Results posted on

2016-03-28

Participant Flow

One subject received an open label study drug under a compassionate use amendment of the protocol. This subject is not reflected in the data analysis for the primary or secondary outcome measures.

Participant milestones

Participant milestones
Measure	Baseline Patients in their first year baseline prior to study drug phase	Placebo Group administered placebo	Rituximab Group administered active drug
Year 1: Baseline Monitoring STARTED	43	0	0
Year 1: Baseline Monitoring COMPLETED	27	0	0
Year 1: Baseline Monitoring NOT COMPLETED	16	0	0
Years 2 & 3: Treatment Randomization STARTED	0	9	18
Years 2 & 3: Treatment Randomization COMPLETED	0	5	7
Years 2 & 3: Treatment Randomization NOT COMPLETED	0	4	11

Reasons for withdrawal

Reasons for withdrawal
Measure	Baseline Patients in their first year baseline prior to study drug phase	Placebo Group administered placebo	Rituximab Group administered active drug
Year 1: Baseline Monitoring Study terminated	7	0	0
Year 1: Baseline Monitoring Withdrawal by Subject	7	0	0
Year 1: Baseline Monitoring Started on DMT	2	0	0
Years 2 & 3: Treatment Randomization Study terminated	0	4	7
Years 2 & 3: Treatment Randomization Withdrawal by Subject	0	0	3
Years 2 & 3: Treatment Randomization Adverse Event	0	0	1

Baseline Characteristics

Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=9 Participants Group administered placebo	Rituximab n=18 Participants Group administered active drug	Baseline n=16 Participants Patients in their first year baseline prior to treatment phase	Total n=43 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants	18 Participants n=7 Participants	16 Participants n=5 Participants	43 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	9 Participants n=7 Participants	11 Participants n=5 Participants	22 Participants n=4 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	9 Participants n=7 Participants	5 Participants n=5 Participants	21 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	18 Participants n=7 Participants	13 Participants n=5 Participants	37 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: 3 months

Population: For the decision to continue trial, only change from baseline to 3 months post-treatment was analyzed in patients who received active drug

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Group administered placebo	Rituximab n=14 Participants Group administered active drug
Analysis of Changes in CSF CXCL13 Induced by Active Treatment (Rituximab) Measured 3 Months After 1st Drug Administration	0 percentage of b cell depletion Interval 0.0 to 0.0	-11.9 percentage of b cell depletion Interval -100.0 to 0.0

PRIMARY outcome

Timeframe: 3 months

Population: For the decision to continue trial, only change from baseline to 3 months post-treatment was analyzed in patients who received active drug.

This outcome is for interim analysis of the efficacy of B cell depletion from the CSF 3 months after giving rituximab or placebo into the cerebrospinal fluid (CSF). It compares concentration of B-cell activating factor (BAFF) before and 3 months after administration of drug into the CSF. We averaged two time-points before treatment (CSF collected 1 year apart, at month -12 and month 0) and compared it to the single time-point (month 3), which was 3 months from the initiation of drug dosing. BAFF is consumed by B cells, therefore effective B cell depletion increases levels of BAFF. The protocol-stipulated threshold for trial continuation was at least 50% increase in CSF BAFF induced by active treatment with significance level p=0.025.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Group administered placebo	Rituximab n=14 Participants Group administered active drug
Analysis of Changes in CSF BAFF Induced by Active Treatment (Rituximab) Measured 3 Months After 1st Drug Administration	4 percentage of BAFF change Interval -11.2 to 20.5	20.9 percentage of BAFF change Interval -0.3 to 24.9

SECONDARY outcome

Timeframe: 3 months

Population: These patients were analyzed for the interim analysis for the efficacy of B cell depletion. Trial stipulated stopping criteria for futility.

This outcome is for interim analysis of the efficacy of B cell depletion from the CSF 3 months after giving rituximab or placebo into the cerebrospinal fluid (CSF). It compares absolute numbers of CSF B cells calculated as proportion of B cells (identified from flow cytometry data) in all immune cells measured in 50-fold concentrated CSF. We averaged two time-points before treatment (CSF collected 1 year apart, at month -12 and month 0) and compared it to the single time-point (month 3), which was 3 months from the initiation of drug dosing.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Group administered placebo	Rituximab n=14 Participants Group administered active drug
Analysis of Changes in CSF B Cell Numbers Between Rituximab and Placebo	-21.6 percentage of b cell depletion Interval -70.4 to 25.4	-50.7 percentage of b cell depletion Interval -83.3 to 49.3

SECONDARY outcome

Timeframe: 24 months

Population: Only 5 patients per group finished Month 24 following 2 years in study drug phase of trial (2 IV doses and 3 IT doses) at the time the study was terminated for futility

Trial was closed prematurely and therefore formal statistical analysis of the acquired clinical outcomes was not performed. EDSS is a clinical rating scale for disability ranging from 0 (normal neurological exam) to 10 (death due to MS) in half point increments.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
Expanded Disability Status Scale (EDSS)	6.5 units on a scale Interval 6.5 to 7.0	6.5 units on a scale Interval 6.5 to 6.5

SECONDARY outcome

Timeframe: 24 months

Population: Only 5 patients per group finished Month 24 following 2 years in study drug phase of trial (2 IV doses and 3 IT doses) at the time the study was terminated for futility.

NRS is a quantitative assessment based on 22 parameters of the neurological exam with scores ranging from maximum of 100 (normal neurological exam) to a minimum of -10 (death due to MS). The higher the score, the better the patient's level of function. trial was closed prematurely and therefore formal statistical analysis of the acquired clinical outcomes makes no sense

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
Scripps Neurological Rating Scale (NRS)	53 units on a scale Interval 52.0 to 55.0	53 units on a scale Interval 53.0 to 61.0

SECONDARY outcome

Timeframe: 24 months

Population: Only 5 patients per group finished Month 24 following 2 years in study drug phase of trial (2 IV doses and 3 IT doses) at the time the study was terminated for futility.

Measure of mobility and leg function based on a timed 25 foot walk. Patient is directed to walk as quickly as possible, with or without an assitive device, to one end of a 25foot course and this is repeated for a total of 2 times. The score is the average of the two completed trials. Trial was closed prematurely and therefore formal statistical analysis of the acquired clinical outcomes makes no sense

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
Timed 25 Foot Walk	18.7 seconds Interval 11.7 to 32.7	19.1 seconds Interval 8.7 to 27.2

SECONDARY outcome

Timeframe: 24 months

Population: Only 5 patients per group finished Month 24 following 2 years in study drug phase of trial (2 IV doses and 3 IT doses) at the time the study was terminated for futility.

Measure of upper extremity (arm and hand) function where patients are asked to pick up one peg at a time, using one hand only, and putting them into the holes as quickly as possible until all the holes are filled and then removing them one at a time as quickly as possible. The dominant and non-dominant hands are tested twice. The time limit per trial is 5 minutes. Trial was closed prematurely and therefore formal statistical analysis of the acquired clinical outcomes makes no sense

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
9-Hole Peg Test	25.1 seconds Interval 23.4 to 48.8	36.7 seconds Interval 36.1 to 45.9

SECONDARY outcome

Timeframe: 24 months

Population: Only 5 patients per group finished Month 24 following 2 years in study drug phase of trial (2 IV doses and 3 IT doses) at the time the study was terminated for futility.

The MSFC is a three-part standardized assessment tool that measures arm, leg, and cognitive function. The scoring is based on the average Z-score for all three parts of the the assessment.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
Multiple Sclerosis Functional Composite (MSFC)	-0.7 Z score Interval -1.2 to 0.2	-0.9 Z score Interval -2.3 to -0.7

SECONDARY outcome

Timeframe: 0 months

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
EDSS	6.5 units on a scale Interval 6.5 to 6.5	6.5 units on a scale Interval 6.0 to 6.5

SECONDARY outcome

Timeframe: 0 Months

Population: Only 5 patients per group finished Month 24 following 2 years in study drug phase of trial (2 IV doses and 3 IT doses) at the time the study was terminated for futility.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
Scripps Neurological Rating Scale (NRS)	57 units on a scale Interval 54.0 to 60.0	59 units on a scale Interval 52.3 to 62.5

SECONDARY outcome

Timeframe: 0 months

Population: Only 5 patients per group finished Month 24 following 2 years in study drug phase of trial (2 IV doses and 3 IT doses) at the time the study was terminated for futility.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
Timed 25 Foot Walk	11.9 seconds Interval 8.2 to 29.8	11.7 seconds Interval 7.6 to 23.6

SECONDARY outcome

Timeframe: 0 months

Population: Only 5 patients per group finished Month 24 following 2 years in study drug phase of trial (2 IV doses and 3 IT doses) at the time the study was terminated for futility.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
9-Hole Peg Test	33.7 seconds Interval 25.8 to 44.5	38.3 seconds Interval 28.8 to 42.4

SECONDARY outcome

Timeframe: 0 Months

Population: Only 5 patients per group finished Month 24 following 2 years in study drug phase of trial (2 IV doses and 3 IT doses) at the time the study was terminated for futility.

The MSFC is a three-part standardized assessment tool that measures arm, leg, and cognitive function. The scoring is based on the average Z-score for all three parts of the the assessment.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Group administered placebo	Rituximab n=5 Participants Group administered active drug
Multiple Sclerosis Functional Composite (MSFC)	-0.8 Z score Interval -1.1 to -0.5	-0.9 Z score Interval -1.6 to -0.4

Adverse Events

Placebo

Serious events: 4 serious events

Other events: 9 other events

Deaths: 0 deaths

Rituximab

Serious events: 4 serious events

Other events: 18 other events

Deaths: 0 deaths

Baseline

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=9 participants at risk Placebo group	Rituximab n=18 participants at risk Group who got active drug	Baseline n=43 participants at risk Patients in their first year baseline prior to study drug phase
Hepatobiliary disorders Gallstones	11.1% 1/9 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/18 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/43 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment
Musculoskeletal and connective tissue disorders Neck and Back Pain	11.1% 1/9 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/18 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/43 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment
Endocrine disorders Elevated Blood Sugar	11.1% 1/9 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/18 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/43 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment
Nervous system disorders Cognitive Decline	11.1% 1/9 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/18 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/43 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Mass	11.1% 1/9 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	5.6% 1/18 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/43 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment
Nervous system disorders Paresthesia	0.00% 0/9 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	5.6% 1/18 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/43 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment
Renal and urinary disorders urinary tract infection	0.00% 0/9 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	5.6% 1/18 • Number of events 2 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/43 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment
Injury, poisoning and procedural complications Post LP Headache	11.1% 1/9 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	5.6% 1/18 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/43 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment
Skin and subcutaneous tissue disorders Cellulitis	0.00% 0/9 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	5.6% 1/18 • Number of events 1 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment	0.00% 0/43 • 36 months First 12 months (Month -12 to Month 0), all patients were untreated; next 24 months (Month 0 to Month 24) patients were randomized to placebo or active treatment

Other adverse events

Additional Information

Dr. Bibiana Bielekova, Prinicipal Investigator

NINDS, NIH

Phone: 301-402-4488

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place