T-regulatory Cells in ALS

NCT04055623 | Unknown Phase 2 DMC FDA Drug

• 1 other identifier: Pro00022167
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief Summary

This study is a randomized, placebo-controlled, phase 2a trial to study the biological activity, safety, and tolerability of regulatory T Lymphocytes (Tregs) taken and expanded outside of the body and returned back to the same person whose Treg were removed, given back by IV (intravenously) and in combination with low-dose IL-2 in people with Amyotrophic Lateral Sclerosis (ALS).

Conditions

ALS (Amyotrophic Lateral Sclerosis)

Keywords

Lou Gehrig's Disease

Outcome Measures

Primary Outcomes (1)

• Change in Treg suppressive function in the blood from baseline to week 24.

  Change in Treg suppressive function on the proliferation of T-effector cells, as measured in percentage at baseline compared to week 24.

  Baseline and week 24.

Secondary Outcomes (3)

• Change in Treg numbers in the blood from baseline to week 24.

  Baseline and week 24

• Tolerability of Treg infusions for 6 months of treatment

  Baseline to week 24.

• Tolerability of ascending doses of Tregs for 6 months of treatment

  Baseline to week 24.

Study Arms (3)

Intravenous infusion of Treg cells + Interleukin-2 injections

EXPERIMENTAL

For the first six months: T-regulatory cells taken from a participant will be increased in numbers outside the body in a lab and then returned back to the same participant through intravenous (IV) infusions once per month. The participant will also take Interleukin-2 (IL2) injections three times per week.

Biological: Monthly autologous Treg cells infusions + 3 times per week Interleukin-2 injections

Intravenous infusion w/Placebo + matching placebo injections

PLACEBO COMPARATOR

For the first six months: Participants will receive matching placebo or inactive intravenous (IV) infusions once per month. The participant will also take a matching inactive placebo injection three times per week.

Other: Monthly placebo infusions + 3 times per week placebo injections

2nd 6-months Open Label: Treg Infusions + IL-2 injections

EXPERIMENTAL

For second six months: All participants will receive their own expanded/increased in numbers Treg cells by monthly infusion plus 3 times per week subcutaneous injections of IL-2.

Biological: Monthly autologous Treg cells infusions + 3 times per week Interleukin-2 injections

Interventions

Monthly autologous Treg cells infusions + 3 times per week Interleukin-2 injections BIOLOGICAL

For the first 6-months of the study: T-regulatory cells taken from a patient, increased in number in a lab, and returned through monthly intravenous (IV) infusions back to same patient + 3 times per week subcutaneous Interleukin-2 injections

Also known as: Individualized therapy Treg cell infusions + Interleukin-2 (IL-2), Proleukin is brand name for IL-2

Intravenous infusion of Treg cells + Interleukin-2 injections

Monthly placebo infusions + 3 times per week placebo injections OTHER

For first 6-months of study: monthly placebo infusions + 3 times per week subcutaneous placebo injections

Also known as: inactive drug

Intravenous infusion w/Placebo + matching placebo injections

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ALS meeting El Escorial criteria for possible, probable, lab-supported probable, or definite ALS.
• At least 18 years old.
• Provided informed consent and authorized use of protected health information (PHI) in accordance with national and local patient privacy regulations.
• Capable of complying with all study procedures, including the study drug delivery procedure, in the Investigator's opinion.
• On a stable regimen of riluzole for at least 30 days at the time of screening. If not on riluzole at the time of study entry, willing to refrain from initiation of the agent for the duration of the trial.
• Patients on edaravone willing to refrain from taking edaravone on the same day as they will receive the Tregs infusion for the duration of the trial. If not on edaravone at the time of study entry, willing to refrain from initiation of the agent for the duration of the trial.
• Medical record documentation of a decline in ALSFRS-R total score of at least two points in the 90 days prior to screening or at least four points over the 180 days prior to screening.
• Forced vital capacity (FVC) ≥65% of predicted capacity for age, height, and gender at screening.
• Patient able and willing to undergo leukapheresis.

You may not qualify if:

• Presence of any of the following clinical conditions that would interfere with the safe conduct of the study, as determined by the Investigator:
• Unstable neurological, cardiovascular, cerebrovascular, pulmonary, renal, hepatic, endocrine, or hematologic disease; active malignancy or infectious disease; or other medical illness.
• Unstable psychiatric illness defined as psychosis (hallucinations or delusions), unstable major depression or substance abuse within 180 days prior to screening.
• Persistent asthma, prior history of acute systemic reactions involving immunoglobulin E (IgE)-dependent mechanisms, history of angioedema, or history of anaphylactic reactions to any medication.
• Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN) at screening.
• Serum creatinine greater than 1.8 mg/dL or creatinine clearance less than 40 mL/min at screening.
• History of or positive test result for human immunodeficiency virus (HIV), hepatitis C virus, or hepatitis B virus (i.e., positive for both hepatitis B surface antigen and hepatitis B core antibody) at screening.
• Tracheostomy.
• If female, breastfeeding, known to be pregnant, planning to become pregnant during the study, or unwilling to use effective contraception for the duration of the trial and for 90 days after treatment.
• If male of reproductive capacity, unwilling to use effective contraception for the duration of the trial and for 90 days after treatment.
• Enrollment in any other interventional study.
• Treatment with another investigational drug, biological agent, or device within 30 days or 5 half-lives of screening, whichever is longer. Patient participation in an observational/non-interventional clinical study is to be discussed with the Medical Monitor.
• Prior gene or cell therapy treatments for ALS.

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead
• Massachusetts General Hospital: collaborator
• The Center for Clinical and Translational Sciences (CCTS) Clinical Research Unit at The University of Texas Health Science Center at Houston: collaborator
• North East Amyotrophic Lateral Sclerosis Consortium: collaborator

Study Sites (2)

Massachusetts General Hospital Neurological Clinical Research Institute

Boston, Massachusetts, 02114, United States

Location

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

Related Publications (11)

• Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005 Apr;6(4):345-52. doi: 10.1038/ni1178.

  PMID: 15785760 BACKGROUND

• Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004 Apr 5;199(7):971-9. doi: 10.1084/jem.20031579.

  PMID: 15067033 BACKGROUND

• Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology. 2006 Mar;117(3):289-300. doi: 10.1111/j.1365-2567.2005.02317.x.

  PMID: 16476048 BACKGROUND

• Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, Liu W, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015 Nov 25;7(315):315ra189. doi: 10.1126/scitranslmed.aad4134.

  PMID: 26606968 BACKGROUND

• Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011 May;134(Pt 5):1293-314. doi: 10.1093/brain/awr074.

  PMID: 21596768 BACKGROUND

• Zhao W, Beers DR, Liao B, Henkel JS, Appel SH. Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol Dis. 2012 Dec;48(3):418-28. doi: 10.1016/j.nbd.2012.07.008. Epub 2012 Jul 17.

  PMID: 22820142 BACKGROUND

• Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, Zhao W, Moore DH, Powell SZ, Appel SH. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med. 2013 Jan;5(1):64-79. doi: 10.1002/emmm.201201544. Epub 2012 Nov 9.

  PMID: 23143995 BACKGROUND

• Beers DR, Zhao W, Wang J, Zhang X, Wen S, Neal D, Thonhoff JR, Alsuliman AS, Shpall EJ, Rezvani K, Appel SH. ALS patients' regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight. 2017 Mar 9;2(5):e89530. doi: 10.1172/jci.insight.89530.

  PMID: 28289705 BACKGROUND

• Alsuliman A, Appel SH, Beers DR, Basar R, Shaim H, Kaur I, Zulovich J, Yvon E, Muftuoglu M, Imahashi N, Kondo K, Liu E, Shpall EJ, Rezvani K. A robust, good manufacturing practice-compliant, clinical-scale procedure to generate regulatory T cells from patients with amyotrophic lateral sclerosis for adoptive cell therapy. Cytotherapy. 2016 Oct;18(10):1312-24. doi: 10.1016/j.jcyt.2016.06.012. Epub 2016 Aug 3.

  PMID: 27497700 BACKGROUND

• Thonhoff JR, Beers DR, Zhao W, Pleitez M, Simpson EP, Berry JD, Cudkowicz ME, Appel SH. Expanded autologous regulatory T-lymphocyte infusions in ALS: A phase I, first-in-human study. Neurol Neuroimmunol Neuroinflamm. 2018 May 18;5(4):e465. doi: 10.1212/NXI.0000000000000465. eCollection 2018 Jul.

  PMID: 29845093 RESULT

• Thonhoff JR, Berry JD, Macklin EA, Beers DR, Mendoza PA, Zhao W, Thome AD, Triolo F, Moon JJ, Paganoni S, Cudkowicz M, Appel SH. Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022 Aug 29;9(6):e200019. doi: 10.1212/NXI.0000000000200019. Print 2022 Nov.

  PMID: 36038262 DERIVED

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Interventions

Interleukin-2

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Stanley H. Appel, MD

  The Methodist Hospital Research Institute

  STUDY DIRECTOR

• Jason R. Thonhoff, MD, PhD

  The Methodist Hospital Research Institute

  PRINCIPAL INVESTIGATOR

• James D. Berry, MD, MPH

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: The study drugs for the first 6-months of the study are (1) Treg cell intravenous (IV) infusions or matching placebo / inactive infusion and (2) subcutaneous interleukin-2 (IL-2) injections or matching placebo / inactive injections; followed by 6-months of Treg infusions and IL-2 injections for all participants.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Houston Methodist Neurological Institute

Model Details: Group 1 entered the first 6-months is the double-blind part of the study where participants are randomized to Treg cell infusions and low dose Interleukin-2 (IL-2) injections OR placebo (inactive) infusions and placebo IL-2 injections and then went into the open label second 6-months of ascending Treg infusions and IL-2 injections. Group 2 went directly into the open label six month trial of ascending Tregs infusions. Group 2 was added due to the pandemic and limits on travel and funding.

Study Record Dates

• First Submitted: August 12, 2019
• First Posted: August 14, 2019
• Study Start: August 7, 2019
• Primary Completion: May 31, 2022
• Study Completion: August 31, 2022
• Last Updated: October 6, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: At the end of the study via data management plan for duration of Treg studies.
• Access Criteria: Request to PI.

Locations

US (2)