Ph1 T-Regulatory Cells in Amyotrophic Lateral Sclerosis | NCT03241784

NCT03241784

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
M.D. Anderson Cancer Center	OTHER

Description Module

Detailed Description

This is Pilot Study will consist of 3 people diagnosed with amyotrophic lateral sclerosis (ALS), who will undergo 4 infusions of autologous expanded Tregs and concomitant subcutaneous injections of Interleukin-2 [IL-2] (2 x 105 IU/m2) 3 times weekly, for 52 weeks or unless the interim analysis confirms or negates the investigational product (IP = Tregs) use.

During the enrollment period up to three research participants will be recruited from patients in our ALS Clinic for screening, baseline measures and leukapheresis. The Treg cell manufacturing will be performed in a current Good Manufacturing Practice (cGMP) laboratory. The first subject will receive infusions of their expanded Tregs (1x106 /kg) with concomitant subcutaneous IL-2 injections (2 x 105 IU/m2) 25 days (+/- 2 days) post leukapheresis. The 2nd subject will begin after the first subject has completed the first 4 weeks and has experienced no untoward effects during this period. Once subjects #1 and #2 have completed the first 4 weeks and no toxic events have occurred they will therefore be considered safely past the first milestone and subject #3 will begin infusions.

Research Participants #1, 2 and 3 will repeat the leukapheresis (under a separate protocol) and undergo Treg infusions at the modified schedule of every 4 weeks, with concomitant subcutaneous injections of IL-2 (2 x 105 IU/m2) 3 times weekly. The subjects will be called on Day 7, and 21. Office visits will be completed on the day after infusions and every two weeks while the subjects are undergoing Treg infusions for clinical evaluation, scoring, and blood draws. The subjects will then be seen during office visits once per month for one year total from their initial baseline visit for clinical evaluation, scoring, and blood draws

Monthly interim analyses will monitor the subjects using validated ALS scales such as the ALS Functional Rating Scale-Revised (ALSFRS-R) and Appel ALS Grading Scale (AALS), which incorporates muscle strength and dysfunction, activities of daily living and pulmonary function. The analyses will also include interim medical history and physical exam, an electrocardiogram (ECG) when indicated, pulmonary function tests (PFTs) such as Forced vital capacity (FVC) and Maximum Inspiratory Pressure (MIP or MIPS), safety labs (such as a complete blood count (CBC), chemistry, liver function, thyroid tests-T4 and TSH) as well as more technical research labs such as T Regulatory Cell and related markers (Th1 and Th17 counts, FoxP3 RNA expression), and Treg Suppression Assays. A prothrombin time (PT) and partial thromboplastin time (PTT) will be performed only if the subject has an abnormal coagulation result at baseline or if the subject is on anti-coagulation therapy.

Adverse Events (AEs) and Serious Adverse Events (SAEs) will be monitoring from the time of consent until end of study or AE/SAE resolution.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Treatment arm	Experimental	All subjects are enrolled in the one arm consisting of infusions of autologous T-regulatory lymphocytes at a dose of 1x10 to the sixth/kg and subcutaneous injections of Interleukin-2 at a dose of 2x10 to the fifth IU/m2 three times a week.	Biological: Autologous T-regulatory lymphocytes Biological: Interleukin-2

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Autologous T-regulatory lymphocytes	Biological	intravenous administration of Autologous T-regulatory lymphocytes at a dose of 1x10 to the sixth /kg.	Treatment arm

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE v4.0) & Medical Dictionary for Regulatory Activities (MedDRA).	Adverse events and serious adverse events related to Treg infusions were monitored throughout the study.	Adverse events related to Treg infusions at Baseline to up to two years or study participation, whichever is occurs first.

Secondary Outcomes

Measure	Description	Time Frame
Appel ALS (AALS) Scale/Grading	The AALS is a published, validated instrument based on objective testing in five categories (bulbar, respiratory function, arm and leg function, and muscle strength) with scores ranging from 30 (normal) to 164 (maximally impaired).	Baseline and at week 15
ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised)

Other Outcomes

Measure	Description	Time Frame
Pulmonary FVC - Exploratory Measure - Percent of Predicted FVC	FVC (Forced Vital Capacity). Reduction of pulmonary function is the primary source of morbidity and mortality in ALS. FVC testing will be used to monitor respiratory function. FVC measures the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. The intent is to report the percent of predicted FVC value.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Age 18 years or older.
Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria (Appendix 1).
Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days (riluzole-naïve subjects are permitted in the study).
Capable of providing informed consent and following trial procedures.
Geographically accessible to the 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 and three months after study completion. Adequate contraception includes: abstinence, hormonal contraception (oral contraception, implanted contraception, injected contraception or other hormonal (patch or contraceptive ring, for example) contraception), intrauterine device (IUD) in place for ≥ 3 months, barrier method in conjunction with spermicide, or another adequate method.
Subjects must agree not to take live attenuated vaccines (including seasonal flu vaccine) 30 days before blood collection.
Available autologous Tregs product with greater than or equal to 50% expression of CD4, CD25 and FoxP3 determined by flow-cytometry.
Subjects must have been previously evaluated and followed clinically by a neuromuscular specialist at Houston Methodist Neurological Institute
Normal Alanine aminotransferase level (ALT)
Normal Serum creatinine level

Exclusion Criteria:

Prior use of cells therapies
Concurrent use of other experimental ALS therapies
Pregnant or breastfeeding or planning to become pregnant or planning a partner's pregnancy.
Other unstable medical or psychiatric illness
Known immune deficiency or history of lymphoma or leukemia
History of lymphopenia.
History of acquired or inherited immune deficiency syndrome, including leukopenia.
History of severe untreated chronic obstructive sleep apnea.
FVC less than 50% predicted at screening.
Exposure to any other agent currently under investigation for the treatment of subjects with ALS (off-label use or investigational) within 30 days of the Baseline Visit.
The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the subject to provide informed consent, according to the PI's judgment, or a history of active substance abuse within the prior year.
Clinically significant history of cardiac, oncologic, hepatic, or renal dysfunction, or other medically significant illness.
The presence of any immunologic or autoimmune disease
Severe cardiac dysfunction defined clinically, or as a left ventricular ejection fraction less than 40% of predicted or abnormal EKG findings.

Name	Affiliation	Role
Stanley H Appel, MD	Houston Methodist Neurological Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Methodist Neurological Institute		Houston	Texas	77030	United States

ID	Title	Description
FG000	Treatment Arm	All subjects with ALS enrolled to one arm and received IV infusions of their autologous T-regulatory lymphocytes at a dose of 1x10 to the sixth/kg & subcutaneous injections of Interleukin-2 at a dose of 2x10 to the fifth IU/m2 three times per week.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Treatment Arm	All subjects are enrolled to an open study arm consisting of autologous T-regulatory lymphocytes IV infusions at a dose of 1x10 to the sixth/kg and subcutaneous injections of Interleukin-2 at a dose of 2x10 to the fifth IU/m2 three times a week.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE v4.0) & Medical Dictionary for Regulatory Activities (MedDRA).

Adverse events and serious adverse events related to Treg infusions were monitored throughout the study.

Posted

Count of Participants

Participants

Adverse events related to Treg infusions at Baseline to up to two years or study participation, whichever is occurs first.

ID	Title	Description
OG000	Treatment Arm	All subjects are enrolled in the one arm consisting of infusions of autologous T-regulatory lymphocytes at a dose of 1x10 to the sixth/kg and subcutaneous injections of Interleukin-2 at a dose of 2x10 to the fifth IU/m2 three times a week. Autologous T-regulatory lymphocytes: intravenous administration of Autologous T-regulatory lymphocytes at a dose of 1x10 to the sixth /kg. Interleukin-2: Subcutaneous Interleukin-2 at a dose of 2x10 to the fifth IU/m2, three times a week.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Treatment Arm	All subjects with ALS enrolled to one arm and received IV infusions of their autologous T-regulatory lymphocytes at a dose of 1x10 to the sixth/kg & subcutaneous injections of Interleukin-2 at a dose of 2x10 to the fifth IU/m2 three times per week.

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Facial ecchymosis post fall	Injury, poisoning and procedural complications	SNOMED CT 270911002	Systematic Assessment	Participant fell due to leg weakness and foot drop secondary to ALS injuring superficial tissues of the face.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Apr 11, 2016	Apr 26, 2019	Prot_SAP_000.pdf
ICF	No	No	Yes	Informed Consent Form	Feb 22, 2017	Apr 8, 2021	ICF_001.pdf

ID	Term
D013118	Spinal Cord Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D016472	Motor Neuron Disease

ID	Term
D007378	Interleukins
D016207	Cytokines
D036341	Intercellular Signaling Peptides and Proteins
D010455	Peptides