Immunosuppression in Amyotrophic Lateral Sclerosis (ALS) (NIPALS2013)

• 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: Emory University
• Collaborator: ALS Association
• Information provided by (Responsible Party): Jonathan D. Glass, M.D., Emory University

• Study Type: Interventional
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Amyotrophic Lateral Sclerosis (ALS)
• Interventions: Drug: Basiliximab; Drug: Methylprednisolone; Drug: Prednisone; Drug: Tacrolimus; Drug: Mycophenolate mofetil
• Enrollment: 31

Participant Flow

Recruitment Details	Participants were recruited for this study from three Northeast ALS Consortium (NEALS) centers in the USA (Emory University in Atlanta, Georgia, Massachusetts General Hospital in Boston, Massachusetts, and University of Massachusetts Medical School in Worcester, Massachusetts. Recruitment occurred between October 2013 and October 2014.
Pre-assignment Details

Arm/Group Title	Immunosuppression Regimen
Arm/Group Description	All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment (described below) and the treatment period lasted for six months. Basiliximab: 20 mg, IV (in the vein) on day 1 and 4. Methylprednisolone: 125 mg, IV (in the vein) on day 1. 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. Tacrolimus: 1-5 mg PO, twice a day (BID) days 2-180. 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.
Period Title: Overall Study
Started	31
Completed	23
Not Completed	8
Reason Not Completed
Adverse Event	1
Death	2
Withdrawal by Subject	2
Disease progression	3

Baseline Characteristics

Arm/Group Title		Immunosuppression Regimen
Arm/Group Description		All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
Overall Number of Baseline Participants		31
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	31 participants
		53.9 (11.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants
	Female	6 19.4%
	Male	25 80.6%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	31 participants
		31 100.0%
Timing of Symptom Onset; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	31 participants
Less than or equal to 24 months prior to screening		20 64.5%
More than 24 months prior to screening		11 35.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With an Average Increase in ALSFRS-R Score of One Point Per Month
Description	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.
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)

Outcome Measure Data

Analysis Population Description

All study participants who received treatment are included in the analysis for this outcome measure, including participants who discontinued treatment early (available ALSFRS-R scores were used).

Arm/Group Title	Immunosuppression Regimen
Arm/Group Description:	Participants were monitored for a three month lead-in period prior to beginning treatment. The Baseline Visit 1 occurred within 21 days after the Screening visit and 3 months prior to receiving the first does of the immunosuppressant regimen. Baseline Visits 2 and 3 occurred 2 and 1 month prior to the start of treatment. All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
Overall Number of Participants Analyzed	31
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%

2. Secondary Outcome

Title	Mean Rate of Change of ALSFRS-R Scores During Treatment Compared to Pre-Treatment
Description	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.
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)

Outcome Measure Data

Analysis Population Description

All study participants who received treatment are included in the analysis for this outcome measure, including participants who discontinued treatment early (available ALSFRS-R scores were used)

Arm/Group Title	Immunosuppression Regimen
Arm/Group Description:	Participants were monitored for a three month lead-in period prior to beginning treatment. The Baseline Visit 1 occurred within 21 days after the Screening visit and 3 months prior to receiving the first does of the immunosuppressant regimen. Baseline Visits 2 and 3 occurred 2 and 1 month prior to the start of treatment. All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
Overall Number of Participants Analyzed	31
Mean (Standard Error); Unit of Measure: units on a scale change per month
	-0.24 (0.23)

3. Secondary Outcome

Title	Mean Rate of Change of Slow Vital Capacity (SVC) During Treatment Compared to Pre-Treatment
Description	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.
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)

Outcome Measure Data

Analysis Population Description

All study participants who received treatment are included in the analysis for this outcome measure.

Arm/Group Title	Immunosuppression Regimen
Arm/Group Description:	Participants were monitored for a three month lead-in period prior to beginning treatment. The Baseline Visit 1 occurred within 21 days after the Screening visit and 3 months prior to receiving the first does of the immunosuppressant regimen. Baseline Visits 2 and 3 occurred 2 and 1 month prior to the start of treatment. All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
Overall Number of Participants Analyzed	31
Mean (Standard Error); Unit of Measure: percent predicted change per month
	-0.18 (0.63)

4. Secondary Outcome

Title	Mean Rate of Change of Hand-Held Dynamometry (HHD) During Treatment Compared to Pre-Treatment
Description	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.
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)

Outcome Measure Data

Analysis Population Description

All study participants who received treatment are included in the analysis for this outcome measure, including participants who discontinued treatment early.

Arm/Group Title	Immunosuppression Regimen
Arm/Group Description:	Participants were monitored for a three month lead-in period prior to beginning treatment. The Baseline Visit 1 occurred within 21 days after the Screening visit and 3 months prior to receiving the first does of the immunosuppressant regimen. Baseline Visits 2 and 3 occurred 2 and 1 month prior to the start of treatment. All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
Overall Number of Participants Analyzed	31
Mean (Standard Error); Unit of Measure: z-score change per month
	-0.05 (0.03)

5. Secondary Outcome

Title	Mean Rate of Change in Grip Strength Treatment Compared to Pre-Treatment
Description	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.
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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Immunosuppression Regimen
Arm/Group Description:	Participants were monitored for a three month lead-in period prior to beginning treatment. The Baseline Visit 1 occurred within 21 days after the Screening visit and 3 months prior to receiving the first does of the immunosuppressant regimen. Baseline Visits 2 and 3 occurred 2 and 1 month prior to the start of treatment. All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
Overall Number of Participants Analyzed	31
Mean (Standard Error); Unit of Measure: pounds change per month
	1.38 (0.65)

6. Secondary Outcome

Title	Mean Rate of Change of T-cell Subsets in Blood Treatment Compared to Pre-Treatment
Description	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.
Time Frame	Pre-Treatment Period (2 months prior to the start of treatment), Treatment Period (Day 1 and Months 1, 2, 4, 6)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Immunosuppression Regimen
Arm/Group Description:	Participants were monitored for a three month lead-in period prior to beginning treatment. The Baseline Visit 1 occurred within 21 days after the Screening visit and 3 months prior to receiving the first does of the immunosuppressant regimen. Baseline Visits 2 and 3 occurred 2 and 1 month prior to the start of treatment. All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
Overall Number of Participants Analyzed	31
Mean (Standard Error); Unit of Measure: fold change per month
	-0.04 (0.03)

7. Secondary Outcome

Title	Collection of Cerebrospinal Fluid for Future Analysis of Cytokine Levels
Description	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.
Time Frame	Pre-Treatment Period (two months prior to the start of treatment), Treatment Period (Months 2 and 6), Post-Treatment Period (Month 12)

Outcome Measure Data

Analysis Population Description

Cerebrospinal fluid was collected from 29 participants and banked for future analysis.

Arm/Group Title	Immunosuppression Regimen
Arm/Group Description:	Participants were monitored for a three month lead-in period prior to beginning treatment. The Baseline Visit 1 occurred within 21 days after the Screening visit and 3 months prior to receiving the first does of the immunosuppressant regimen. Baseline Visits 2 and 3 occurred 2 and 1 month prior to the start of treatment. All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
Overall Number of Participants Analyzed	31
Measure Type: Count of Participants; Unit of Measure: Participants
	29 93.5%

8. Secondary Outcome

Title	Collection of Blood for Future Analysis of Peripheral Blood Mononuclear Cells (PBMCs)
Description	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.
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)

Outcome Measure Data

Analysis Population Description

Blood was collected for all 31 participants and banked for future use.

Arm/Group Title	Immunosuppression Regimen
Arm/Group Description:	Participants were monitored for a three month lead-in period prior to beginning treatment. The Baseline Visit 1 occurred within 21 days after the Screening visit and 3 months prior to receiving the first does of the immunosuppressant regimen. Baseline Visits 2 and 3 occurred 2 and 1 month prior to the start of treatment. All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
Overall Number of Participants Analyzed	31
Measure Type: Count of Participants; Unit of Measure: Participants
	31 100.0%

Adverse Events

Time Frame	Participants were monitored for adverse events (AEs) from the time they signed the consent form until completion of their participation in the study (defined as death, withdrawal of consent, loss to follow up, early termination due to other reasons, or completion of the entire study).
Adverse Event Reporting Description	For the purposes of this study, an adverse event is considered any unfavorable and unintended sign (including clinically significant abnormal laboratory findings), symptom, or disease temporally associated with a study, whether or not the adverse event is considered to be related to the drug product under examination.
Arm/Group Title	Immunosuppression Regimen
Arm/Group Description	All participants received the same treatment intervention consisting of basiliximab, methylprednisolone, prednisone, tacrolimus and mycophenolate mofetil. Doses of each medication varied by the day of treatment and the treatment period lasted for six months.
All-Cause Mortality
	Immunosuppression Regimen
	Affected / at Risk (%)
Total	2/31 (6.45%)
Serious Adverse Events
	Immunosuppression Regimen
	Affected / at Risk (%)	# Events
Total	5/31 (16.13%)
Cardiac disorders
Asymptomatic T-wave inversions with troponin elevation * [1]	1/31 (3.23%)	1
Musculoskeletal and connective tissue disorders
Hospitalization due to knee injury from a fall *	1/31 (3.23%)	1
Nervous system disorders
Hospital admission for dehyration due to dysphagia from ALS *	1/31 (3.23%)	1
Renal and urinary disorders
Hospitalization due to a kidney stone *	1/31 (3.23%)	1
Respiratory, thoracic and mediastinal disorders
Hospitalization due to pulmonary embolism *	1/31 (3.23%)	1
Hospitalization due to bilateral pneumonia *	1/31 (3.23%)	2
* Indicates events were collected by non-systematic assessment; [1] Asymptomatic T-wave inversions with slight troponin elevation; no indication of an acute cardiac event
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Immunosuppression Regimen
	Affected / at Risk (%)	# Events
Total	31/31 (100.00%)
Gastrointestinal disorders
Diarrhea *	13/31 (41.94%)	17
General disorders
Fall *	17/31 (54.84%)	48
Headache *	11/31 (35.48%)	16
Nausea *	4/31 (12.90%)	5
Infections and infestations
Cold Sore *	1/31 (3.23%)	4
Musculoskeletal and connective tissue disorders
Muscular Weakness *	12/31 (38.71%)	27
Muscular Spasms *	11/31 (35.48%)	14
Back Pain *	10/31 (32.26%)	12
Renal and urinary disorders
Renal insufficiency (elevated creatinine) *	1/31 (3.23%)	1
Respiratory, thoracic and mediastinal disorders
Tracheal bronchitis *	1/31 (3.23%)	1
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Jonathan Glass, MD
• Organization: Emory University
• Phone: 404-727-3507
• EMail: jglas03@emory.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Jonathan D. Glass, M.D., Emory University
• ClinicalTrials.gov Identifier: NCT01884571
• Other Study ID Numbers: IRB00064218; NIP-ALS-2013 ( Other Identifier: Other ); 2013P000981 ( Other Identifier: Other )
• First Submitted: June 19, 2013
• First Posted: June 24, 2013
• Results First Submitted: May 12, 2017
• Results First Posted: July 31, 2017
• Last Update Posted: November 6, 2017