T-regulatory Cells in ALS

Study Overview
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Brief Summary
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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).

Detailed Description
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Based on data collected in a previous study with a small group of patients, evidence was found to show that interfering with the immune system using Treg cells slowed ALS disease progression. It is known that Treg cell numbers and function are reduced in patients with ALS and in some patients with lower Treg cells, they have a more marked rapid progression of their ALS. For this study, there are two sites (in Houston, Texas and Boston, Massachusetts) in which Tregs will be taken from participants, increased or expanded outside the body, and then re-administered back to the participants from which the Tregs came. This study has two parts and due to the pandemic two groups [Group 1 and Group 2]: The first period is a 6-month, randomized, placebo-controlled part of the study to study the biological activity, safety, and tolerability of the monthly expanded Tregs administered intravenously (IV) OR placebo (saline) administered intravenously plus subcutaneous low-dose Interleukin-2 (IL-2) OR subcutaneous placebo (saline) injections in 12 adults with ALS. IL2 helps regulate the immune system's white blood cells. [Group 1 only.] The second period is a 6-month OPEN-LABEL part of the study (no placebo) in which all participants will receive their own expanded Treg cells administered intravenously in combination with subcutaneous low-dose IL-2 at the following schedule: single dose of Treg cells twice (once per month with three IL2 injections per week); followed by double the dose of Treg cells twice (once per month with three IL2 injections per week); followed by triple the dose of Treg cells twice (one per month with three IL2 injection per week); followed by a 1 month follow-up safety visit after the last triple dose of Tregs with was received and the last set of IL2 injections three times per week injections. [Group 1 and Group 2.] Groups: GROUP 1 will go through the double-blind part of the study (receive either Tregs infusions and IL2 injections OR saline infusions and saline injections) for six months and open label part of the study (receive Treg injections and IL2 injections) for six months. GROUP 2 will receive only the open label (Tregs infusions and IL2 injections) for six months. This study is studying whether the enhancement of Treg numbers and function will slow disease progression. In the first study of Tregs, we completed a single-center, open-label phase I study of Tregs from people with ALS. Tregs were increased outside the body and returned back to the individual Treg owners in multiple doses every 2 to 4 weeks. This early study provided evidence in a small group of patients that treatment with autologous Tregs may be effective in slowing ALS progression.

Official Title
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Phase 2a Study of the Expansion and Infusion of Autologous T-Regulatory Cells in Amyotrophic Lateral Sclerosis

Conditions
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ALS (Amyotrophic Lateral Sclerosis)

Intervention / Treatment
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* Biological: Monthly autologous Treg cells infusions + 3 times per week Interleukin-2 injections
* Other: Monthly placebo infusions + 3 times per week placebo injections
* Biological: Monthly autologous Treg cells infusions + 3 times per week Interleukin-2 injections


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous infusion of Treg cells + Interleukin-2 injections<br>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<br>* 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<br>* Other names: Proleukin is brand name for IL-2;|
| Placebo Comparator: Intravenous infusion w/Placebo + matching placebo injections<br>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<br>* For first 6-months of study: monthly placebo infusions + 3 times per week subcutaneous placebo injections<br>* Other names: inactive drug;|
| Experimental: 2nd 6-months Open Label: Treg Infusions + IL-2 injections<br>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<br>* For the second 6-months of the study: all participants will receive T-regulatory cells taken from the patient, that have been increased in number in a lab, and returned through monthly intravenous (IV) infusions back to same patient (Treg cell owner) + 3 times per week subcutaneous Interleukin-2 injections.<br>* Other names: Proleukin is the brand name for IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Treg numbers in the blood from baseline to week 24. | Change in Treg numbers in the blood at baseline compared to week 24; measured in % of total CD4+ cells. | Baseline and week 24 | 
| Tolerability of Treg infusions for 6 months of treatment | Defined as the percentage of participants who complete the 6-month RCT. | Baseline to week 24. | 
| Tolerability of ascending doses of Tregs for 6 months of treatment | Defined as the percentage of participants who complete the ascending doses of Tregs. | Baseline to week 24. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lou Gehrig's Disease