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Immunosuppression in Amyotrophic Lateral Sclerosis (ALS) (NIPALS2013)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01884571
Recruitment Status : Completed
First Posted : June 24, 2013
Results First Posted : July 31, 2017
Last Update Posted : November 6, 2017
Sponsor:
Collaborator:
ALS Association
Information provided by (Responsible Party):
Jonathan D. Glass, M.D., Emory University

Tracking Information
First Submitted Date  ICMJE June 19, 2013
First Posted Date  ICMJE June 24, 2013
Results First Submitted Date  ICMJE May 12, 2017
Results First Posted Date  ICMJE July 31, 2017
Last Update Posted Date November 6, 2017
Study Start Date  ICMJE October 2013
Actual Primary Completion Date January 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 2, 2017)
Number of Participants With an Average Increase in ALSFRS-R Score of One Point Per Month [ Time Frame: Pre-Treatment Period (3 months prior to the start of treatment, 2 months prior to the start of treatment, and 1 month prior to the start of treatment), Treatment Period (Day 1 and then monthly until Month 6) ]
The ALS Functional Rating Scale - Revised (ALSFRS-R) is an ordinal rating scale (0 through 4) used to determine the ALS patient's self assessment of their ability and need for assistance in 12 activities or functions. This is a validated scale, both in person and by phone, which provides a total score (best of 48) from four sub-scores which assess speech and swallowing, (bulbar function), use of upper extremities (cervical function), gait and turning in bed (lumbar function), and breathing (respiratory function). A clinical response is defined as a rate of change of ALSFRS-R of +6 points over 6 months (mean of +1 point per month), where typically patients with ALS have a decline in ALSFRS-R by an average of -1/month.
Original Primary Outcome Measures  ICMJE
 (submitted: June 19, 2013)
Change in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) [ Time Frame: Screening, Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. Telephone ALSFRS-R will be collected at Months 7, 9 and 11. ]
The Revised ALS Functional Rating Scale - Revised (ALSFRS-R) is an ordinal rating scale (0 through 4) used to determine the ALS patient's self assessment of their ability and need for assistance in 12 activities or functions. This is a validated scale, both in person and by phone, which provides a total score (best of 48) from four sub-scores which assess speech and swallowing, (bulbar function), use of upper extremities (cervical function), gait and turning in bed (lumbar function), and breathing (respiratory function). A clinical response will be defined as a rate of change of ALSFRS-R of +6 points over 6 months (mean of +1 point per month), where typically patients with ALS have a decline in ALSFRS-R by an average of -1/month.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2017)
  • Mean Rate of Change of ALSFRS-R Scores During Treatment Compared to Pre-Treatment [ Time Frame: Pre-Treatment Period (3 months prior to the start of treatment, 2 months prior to the start of treatment, and 1 month prior to the start of treatment), Treatment Period (Day 1 and then monthly until Month 6) ]
    The ALS Functional Rating Scale - Revised (ALSFRS-R) is an ordinal rating scale (0 through 4) used to determine the ALS patient's self assessment of their ability and need for assistance in 12 activities or functions. This is a validated scale, both in person and by phone, which provides a total score from four sub-scores which assess speech and swallowing, (bulbar function), use of upper extremities (cervical function), gait and turning in bed (lumbar function), and breathing (respiratory function). Total scores range from 0 (most impaired) to 48 (normal ability). ALSFRS-R was measured during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. A negative value means that scores during treatment were lower than pre-treatment scores, indicating a decline in ability over time.
  • Mean Rate of Change of Slow Vital Capacity (SVC) During Treatment Compared to Pre-Treatment [ Time Frame: Pre-Treatment Period (3 months prior to the start of treatment, 2 months prior to the start of treatment, and 1 month prior to the start of treatment), Treatment Period (Day 1 and then monthly until Month 6) ]
    Vital capacity (VC), percent of predicted normal, was determined using the slow VC method. SVC measures the amount of air exhaled following a deep breath. For this test, participants hold a mouthpiece in their mouth, breathe in deeply, and breathe out as much air as they can. The test was done seated in a chair and then repeated while lying on an exam table at the Screening Visit. For all other visits, this test was done while seated in a chair. This test takes 15-20 minutes. SVC was measured during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. SVC is a way to measure respiratory insufficiency in persons with ALS and SVC decreases as ALS progresses. A negative value means that scores during treatment were lower than pre-treatment scores, indicating a decline over time.
  • Mean Rate of Change of Hand-Held Dynamometry (HHD) During Treatment Compared to Pre-Treatment [ Time Frame: Pre-Treatment Period (3 months prior to the start of treatment, 2 months prior to the start of treatment, and 1 month prior to the start of treatment), Treatment Period (Day 1 and then monthly until Month 6) ]
    Hand held dynamometry (HHD) is a measure of muscle strength and scores decrease as ALS progresses. Six proximal muscle groups were examined bilaterally in both upper and lower extremities. Mean and standard deviation for each muscle group are established from the initial values for each participant. Strength determinations were converted to Z scores and averaged to provide an HHD megascore. The Z-score indicates the number of standard deviations away from the mean of 0. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. HHD was measured during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. A negative value means that scores during treatment were lower than pre-treatment scores, indicating a decline in strength over time.
  • Mean Rate of Change in Grip Strength Treatment Compared to Pre-Treatment [ Time Frame: Pre-Treatment Period (3 months prior to the start of treatment, 2 months prior to the start of treatment, and 1 month prior to the start of treatment), Treatment Period (Day 1 and then monthly until Month 6) ]
    Hand grip was measured using a study approved dynamometer to test the maximum isometric strength of the hand and forearm muscles. The grip strength of the left and right hands were analyzed together. Grip strength was measured during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. Grip strength is a measurement of muscle strength and declines as ALS progresses. A positive value means that scores during treatment were higher than pre-treatment scores, indicating an increase in grip strength over time.
  • Mean Rate of Change of T-cell Subsets in Blood Treatment Compared to Pre-Treatment [ Time Frame: Pre-Treatment Period (2 months prior to the start of treatment), Treatment Period (Day 1 and Months 1, 2, 4, 6) ]
    Blood was collected for ribonucleic acid (RNA) and the mean rate of decline of T-cells during the 6 month treatment period compared to the pre-treatment period was assessed (blood was collected twice during the 3-month long lead in period). The precise role that T-cells have in ALS is unknown and this study aims to further the understanding of how T-cells operate in persons with ALS. T-cell measurement is a ratio where the relative expression levels of FOXP3 messenger ribonucleic acid (mRNA) was calculated using the Comparative CT Method (ΔΔCT Method), normalizing to β-actin. Samples were obtained during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. A negative value means that scores during treatment were lower than pre-treatment scores, indicating a decline in T-cells over time.
  • Collection of Cerebrospinal Fluid for Future Analysis of Cytokine Levels [ Time Frame: Pre-Treatment Period (two months prior to the start of treatment), Treatment Period (Months 2 and 6), Post-Treatment Period (Month 12) ]
    Lumbar punctures (LPs) were performed to collect cerebrospinal fluid (CSF). CSF is banked for future use to characterize immune system markers and to further the understanding of the immune factors that contribute to disease progression in ALS. Cytokines are markers of neuroinflammation and can be categorized as neurotoxic or neuroprotective. The role that cytokines play in in ALS progression is still not yet fully understood.
  • Collection of Blood for Future Analysis of Peripheral Blood Mononuclear Cells (PBMCs) [ Time Frame: Pre-Treatment Period (2 months prior to the start of treatment), Treatment Period (Day 1 and Months 1, 2, 4, 6), Post-Treatment Period (Months 8 and 12) ]
    Blood was drawn and banked for future use in order to characterize immune system markers and further the understanding of the immune factors that contribute to disease progression in ALS.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2013)
  • Change in Slow Vital Capacity (SVC) [ Time Frame: Screening, Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. ]
    Vital capacity (VC), percent of predicted normal, will be determined using the slow VC method. SVC measures the amount of air exhaled following a deep breath. For this test, participants will hold a mouthpiece in their mouth, breathe in deeply, and breathe out as much air as they can. The test will be done seated in a chair and then repeated while e lying on an exam table at the Screening Visit. For all other visits, this test will be done with seated in a chair. This test will take 15-20 minutes. At the Screening visit, eligibility for Group A will be determined utilizing upright SVC.
  • Change in Negative Inspiratory Force (NIF) [ Time Frame: Screening, Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. ]
    The negative inspiratory force (NIF) is an isometric measure of the strength of respiratory muscles, obtained by having the participant inhale as strongly as possible with the mouth against a mouthpiece. NIF will be recorded in the upright position.
  • Change in Hand-Held Dynamometry (HHD) [ Time Frame: Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. ]
    Hand held dynamometry (HHD) will be used as a quantitative measure of muscle strength for this study. Six proximal muscle groups will be examined bilaterally in both upper and lower extremities (shoulder flexion, elbow flexion, elbow extension, hip flexion, knee flexion, and knee extension), all of which have been validated against maximum voluntary isometric contraction (MVIC) testing. In addition, wrist extension, first dorsal interosseous contraction and ankle dorsiflexion will be measured bilaterally; these muscles are often affected in Amyotrophic Lateral Sclerosis.
  • Change in Cytokine Levels in Cerebrospinal Fluid (CSF) [ Time Frame: Baseline Visit 2 and Months 2, 6 and 12. ]
    Lumbar punctures (LPs) will be done to collect cerebrospinal fluid in order to characterize markers of the participants immune system and further the understanding of the immune factors that contribute to disease progression in ALS
  • Collection of Peripheral Blood Mononuclear Cells (PBMCs) in Blood [ Time Frame: Baseline Visit 2, Day 1, Months 1, 2, 4, 6, 8 and 12, and at the Final Safety Visit if a subject discontinues study drug early. ]
    Blood will be drawn in order to characterize markers of the participants immune system and further the understanding of the immune factors that contribute to disease progression in ALS.
  • Change in Left Grip Strength [ Time Frame: Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. ]
    Left hand grip will be measured using a study approved dynamometer to test the maximum isometric strength of the hand and forearm muscles.
  • Change in Right Grip Strength [ Time Frame: Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. ]
    Right Hand grip will be measured using a study approved dynamometer to test the maximum isometric strength of the hand and forearm muscles.
  • Change in Antibody levels in Cerebrospinal Fluid (CSF) [ Time Frame: Baseline Visit 2 and Months 2, 6 and 12. ]
    Lumbar punctures (LPs) will be done to collect cerebrospinal fluid in order to characterize markers of the participants immune system and further the understanding of the immune factors that contribute to disease progression in ALS
  • Collection of Ribonucleic Acid (RNA) in Blood [ Time Frame: Baseline Visit 2, Day 1, and Months 1, 2, 4, 6, 8 and 12, and at the Final Safety Visit if a subject discontinues study drug early ]
    Blood will be collected for ribonucleic acid (RNA).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immunosuppression in Amyotrophic Lateral Sclerosis (ALS)
Official Title  ICMJE A Novel Immunosuppression Intervention for the Treatment of Amyotrophic Lateral Sclerosis (ALS)
Brief Summary This is a multicenter, 15-month study evaluating the effect of immunosuppression treatment on the rate of change on the ALS Functional Rating Scale (Revised) (ALSFRS-R) score in up to 33 subjects with Amyotrophic Lateral Sclerosis (ALS).
Detailed Description

In an ongoing safety trial of neural stem cell injections into the spinal cord of patients with ALS at Emory University, Atlanta, Georgia, one patient has demonstrated clear improvement by objective clinical and electrophysiological measures, a finding that is unheard of in patients with ALS.

This patient had an improvement in ALSFRS-R by 1.4 points per month. In 826 historical controls from the Northeast ALS Consortium (NEALS) and the Western ALS Consortium (WALS) database where ALSFRS-R was documented at 2 or more visits, there have been no patients that have shown improvement in ALSFRS as seen in this case. Additionally, 5 patients in the stem cell trial who were not on mechanical ventilators at the time of surgery seem to have very slow disease progression as compared to the expectation from current understanding of typical disease course. This observation raises consideration for a disease-modifying effect of the novel immunosuppression regimen used in this trial. Also, given that ALS is clinically an extraordinarily heterogeneous disease, the diagnosis of ALS may represent a group of phenotypically similar but pathogenically variable disorders. It is possible that there exists a subset of patients with an immune-responsive ALS subtype that has not been previously recognized.

Recent studies have furthered the understanding of the immune mechanisms that contribute to ALS progression. Microglia and lymphocytes have both neurotoxic and neuroprotective functions depending on activation states and physiologic conditions within the nervous system. Therefore, targeted immunotherapies that proportionally suppress neurotoxic immune elements, while sparing or promoting protective elements, seemingly have more potential to modify disease course in ALS than previously tested regimens. It is postulated that the immunosuppression treatment given to the stem cell patients may have exhibited neuroprotective effects by favorably promoting the ratio of regulatory T cells and other protective immune mediators in relation to neurotoxic immune modulators. It is hoped that this trial will optimize the chance of replicating these findings and advance knowledge about the complex changes that occur within the immune system in patients with ALS before and after treatment with an immunosuppression regimen.

The primary outcome measure will be rate of change of ALSFRS-R. A clinical response will be defined as a rate of change of ALSFRS-R of +6 points over a 6 month period (mean of change of +1 point per month).

Secondary outcome measures will include slow vital capacity (SVC), grip strength, and hand held dynamometry (HHD). The change in rate of progression in clinical measures will be monitored to look for a potential disease-modifying effect of the immunosuppression regimen. Blood and cerebrospinal fluid immune system markers will be also be studied.

If a clinical response is seen among study participants following treatment, further analyses will be conducted to explore any differential effects of immunosuppression in participants with early-stage disease and later-stage disease. To ensure adequate numbers of participants for conditional analyses stratifying by symptom onset date, participants will be enrolled based on symptom onset within 24 months of the screening visit or more than 24 months before screening. All participants will have the same treatment and will be treated as a single group for the analyses of the main study outcomes.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Amyotrophic Lateral Sclerosis (ALS)
Intervention  ICMJE
  • Drug: Basiliximab
    20 mg, IV (in the vein) on day 1 and 4.
    Other Name: Simulect
  • Drug: Methylprednisolone
    125 mg, IV (in the vein) on day 1.
    Other Name: Solumedrol
  • Drug: Prednisone
    60 mg PO (by mouth) on days 2-7, 40 mg PO days 8-14, 20 mg PO days 15-21, and 10mg PO days 22-28.
    Other Names:
    • Deltasone
    • Orasone
  • Drug: Tacrolimus
    1-5 mg PO, twice a day (BID) days 2-180.
    Other Name: Prograf
  • Drug: Mycophenolate mofetil
    500 mg PO, BID days 2-7, 500 mg PO each morning and 1000 mg each night, days 8-14, 1000 mg PO BID days 15-180.
    Other Name: Cellcept
Study Arms  ICMJE Experimental: Immunosuppression Regimen
Basiliximab Methylprednisolone Prednisone Tacrolimus Mycophenolate mofetil
Interventions:
  • Drug: Basiliximab
  • Drug: Methylprednisolone
  • Drug: Prednisone
  • Drug: Tacrolimus
  • Drug: Mycophenolate mofetil
Publications * Fournier CN, Schoenfeld D, Berry JD, Cudkowicz ME, Chan J, Quinn C, Brown RH, Salameh JS, Tansey MG, Beers DR, Appel SH, Glass JD. An open label study of a novel immunosuppression intervention for the treatment of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2018 May;19(3-4):242-249. doi: 10.1080/21678421.2017.1421666. Epub 2018 Jan 8.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 30, 2017)
31
Original Estimated Enrollment  ICMJE
 (submitted: June 19, 2013)
30
Actual Study Completion Date  ICMJE January 2016
Actual Primary Completion Date January 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria for participants with symptom onset within the past 24 months:

  • Male or female patients 18-65 years of age.
  • ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial Criteria.
  • Symptom onset ≤ 24 months from screening visit.
  • A score of ≥38 on the Revised ALS Functional Rating Scale.
  • Slow vital capacity (SVC) measure >80% of predicted for gender, height and age at screening.
  • Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days, prior to the screening visit (riluzole-naïve subjects are permitted in the study).
  • Negative tuberculosis (TB) test within 3 months of Screening Visit.
  • Subjects medically able to undergo lumbar puncture (LP) as determined by the investigator (i.e., no bleeding disorder, allergy to local anesthetics, or a skin infection at or near the LP site).
  • Capable of providing informed consent and following study procedures.
  • Women must not be able to become pregnant (e.g. post menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study.
  • Women of childbearing potential must have a negative pregnancy test at screening and be non-lactating.
  • Geographic accessibility to the study site.

Inclusion Criteria for participants with symptom onset greater than 24 months before screening:

  • Male or female patients age 18 or older.
  • ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial Criteria.
  • Symptom onset >24 months from screening visit.
  • Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days, prior to the screening visit (riluzole-naïve subjects are permitted in the study).
  • Negative tuberculosis (TB) test within 3 months of Screening Visit.
  • Subjects medically able to undergo lumbar puncture (LP) as determined by the investigator (i.e., no bleeding disorder, allergy to local anesthetics, or a skin infection at or near the LP site).
  • Capable of providing informed consent and following study procedures.
  • Geographic accessibility to the study site.
  • Women must not be able to become pregnant (e.g. post menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study.
  • Women of childbearing potential must have a negative pregnancy test at screening and be non-lactating.

Exclusion Criteria

  • Prior use of basiliximab, solumedrol, prednisone, tacrolimus or mycophenolate mofetil within 30 days of the Screening Visit.
  • Known allergy or sensitivity to basiliximab, solumedrol, prednisone, tacrolimus or mycophenolate mofetil or a formulation of one of these drugs.
  • Treatment with an immunosuppressant medication within 30 days of the Screening Visit.
  • Active peptic ulcer disease.
  • Any medical disorder that would make immunosuppression contraindicated including, but not limited to, human immunodeficiency virus (HIV), tuberculosis, or evidence of active cytomegalovirus (CMV) or infection.
  • Subjects who have a diaphragm pacing system (DPS).
  • Women who are pregnant, breastfeeding, or planning to become pregnant in the next 12 months.
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • Use of invasive or non-invasive mechanical ventilation (including Continuous Positive Airway Pressure (CPAP) or Bi-level Positive Airway Pressure (BiPAP)) for any part of the day or night prior to the Screening Visit (participants with symptom onset within past 24 months only).
  • Exposure to any other agent currently under investigation for the treatment of patients with ALS (off-label use or investigational) within 30 days of the Screening Visit.
  • Inability to safely complete study activities based on the discretion of the site investigator.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01884571
Other Study ID Numbers  ICMJE IRB00064218
NIP-ALS-2013 ( Other Identifier: Other )
2013P000981 ( Other Identifier: Other )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Jonathan D. Glass, M.D., Emory University
Study Sponsor  ICMJE Emory University
Collaborators  ICMJE ALS Association
Investigators  ICMJE
Principal Investigator: Jonathan D Glass, MD Emory University
Principal Investigator: Christina N Fournier, MD Emory University
PRS Account Emory University
Verification Date November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP