Immunosuppression in Amyotrophic Lateral Sclerosis (ALS) (NIPALS2013)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
ALS Association
Information provided by (Responsible Party):
Jonathan D. Glass, M.D., Emory University
ClinicalTrials.gov Identifier:
NCT01884571
First received: June 19, 2013
Last updated: September 8, 2014
Last verified: September 2014
  Purpose

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).


Condition Intervention Phase
Amyotrophic Lateral Sclerosis (ALS)
Drug: Basiliximab
Drug: Methylprednisolone
Drug: Prednisone
Drug: Tacrolimus
Drug: Mycophenolate mofetil
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Novel Immunosuppression Intervention for the Treatment of Amyotrophic Lateral Sclerosis (ALS)

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
    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 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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Blood will be collected for ribonucleic acid (RNA).


Estimated Enrollment: 30
Study Start Date: October 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Immunosuppression Regiment
Basiliximab Methylprednisolone Prednisone Tacrolimus Mycophenolate mofetil
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.
Drug: Tacrolimus
1-5 mg PO, BID (twice a day) 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

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 allow the learning more about the complex changes that occur within the immune system in patients with ALS before and after treatment with an immunosuppression regimen.

The primary objective of this study is to assess the clinical response rate of a novel immunosuppression regimen in a subset of ALS patients.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Group A Inclusion Criteria:

  • 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.

Group B Inclusion Criteria

  • 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.

Group A & B 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 (Group A 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01884571

Locations
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
University of Massachusetts Medical School
Worcester, Massachusetts, United States, 01655
Sponsors and Collaborators
Emory University
ALS Association
Investigators
Principal Investigator: Jonathan D Glass, MD Emory University
Principal Investigator: Christina N Fournier, MD Emory University
  More Information

Additional Information:
No publications provided

Responsible Party: Jonathan D. Glass, M.D., Director, Emory ALS Clinic, Emory University
ClinicalTrials.gov Identifier: NCT01884571     History of Changes
Other Study ID Numbers: 2013P000981, NIP-ALS-2013
Study First Received: June 19, 2013
Last Updated: September 8, 2014
Health Authority: United States: Institutional Review Board
United States: Data and Safety Monitoring Board

Keywords provided by Emory University:
Immunosuppression
ALS

Additional relevant MeSH terms:
Amyotrophic Lateral Sclerosis
Sclerosis
Motor Neuron Disease
Central Nervous System Diseases
Metabolic Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neuromuscular Diseases
Pathologic Processes
Proteostasis Deficiencies
Spinal Cord Diseases
TDP-43 Proteinopathies
Basiliximab
Methylprednisolone
Methylprednisolone acetate
Methylprednisolone Hemisuccinate
Mycophenolate mofetil
Mycophenolic Acid
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Prednisone
Tacrolimus
Anti-Inflammatory Agents
Antibiotics, Antineoplastic
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents

ClinicalTrials.gov processed this record on October 29, 2014