A Pilot Study of Inosine in Amyotrophic Lateral Sclerosis (ALS)

• ClinicalTrials.gov Identifier: NCT02288091
• Recruitment Status: Completed
• First Posted: November 11, 2014
• Results First Posted: October 2, 2017
• Last Update Posted: November 6, 2017
• Sponsor: Massachusetts General Hospital
• Collaborators: The Salah Foundation; MGH cure ALS Fund
• Information provided by (Responsible Party): Sabrina Paganoni, M.D., Massachusetts General Hospital

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Amyotrophic Lateral Sclerosis
• Intervention: Drug: Inosine
• Enrollment: 32

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Period Title: Overall Study
Started	32
Randomized/Treated	25
Completed	24
Not Completed	8
Reason Not Completed
Lost to Follow-up	1
Screen fail	7

Baseline Characteristics

Arm/Group Title		Open-label
Arm/Group Description		Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Overall Number of Baseline Participants		25
Baseline Analysis Population Description		32 subjects were consented, however, 25 patients were randomized/treated to received the study drug.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	25 participants
		61.2 (8.4)
Sex: Female, Male [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	25 participants
	Female	18 72.0%
	Male	7 28.0%
		[1] Measure Analysis Population Description: 32 subjects were consented, however, 25 patients were randomized/treated to received the study drug.
Ethnicity (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	25 participants
	Hispanic or Latino	1 4.0%
	Not Hispanic or Latino	24 96.0%
	Unknown or Not Reported	0 0.0%
		[1] Measure Analysis Population Description: 32 subjects were consented, however, 25 patients were randomized/treated to received the study drug.
Race (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	25 participants
	American Indian or Alaska Native	0 0.0%
	Asian	1 4.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	1 4.0%
	White	23 92.0%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%
		[1] Measure Analysis Population Description: 32 subjects were consented, however, 25 patients were randomized/treated to received the study drug.
Region of Enrollment [1]; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	25 participants
		25
		[1] Measure Analysis Population Description: 32 subjects were consented, however, 25 patients were randomized/treated to received the study drug.

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing Adverse Events
Description	Safety will be assessed by the occurrence of adverse events.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

No expected adverse events of special interest, such as kidney stones and gout, occurred during the course of the study. However, twenty-two (22) out of twenty-five (25) participants did experience an adverse event during the course of the study.

Arm/Group Title	Open-label
Arm/Group Description:	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Overall Number of Participants Analyzed	25
Measure Type: Count of Participants; Unit of Measure: Participants
	22 88.0%

2. Primary Outcome

Title	Tolerability to Complete the Entire 12 Week Study on Study Drug.
Description	Tolerability will be defined as the ability of subjects to complete the entire 12-week study on study drug.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Twenty-four (24) out of twenty-five (25) participants completed 12 weeks of study drug treatment.

Arm/Group Title	Open-label
Arm/Group Description:	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Overall Number of Participants Analyzed	25
Measure Type: Count of Participants; Unit of Measure: Participants
	24 96.0%

3. Secondary Outcome

Title	Blood Biomarkers (GSH) at Baseline and Week 12
Description	Blood samples will be obtained at baseline and after 12 weeks of treatment to measure biomarkers of oxidative stress and damage such as glutathione (GSH).
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Two (2) subjects did not have blood drawn for GSH analysis at the Baseline Visit. Five (5) subjects did not have blood drawn for GSH analysis at the Week 12 visit. These missing samples are due to technical issues, such as a difficult blood draw or issue with sample processing.

Arm/Group Title		Open-label
Arm/Group Description:		Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Overall Number of Participants Analyzed		23
Mean (Standard Deviation); Unit of Measure: ƥM
Glutathione at Baseline	Number Analyzed	23 participants
		94.0 (28.4)
Glutathione at Week 12	Number Analyzed	20 participants
		84.5 (42.6)

4. Secondary Outcome

Title	Neuroimaging Biomarkers at Baseline and Week 12
Description	Magnetic resonance spectroscopy (MRS) will be performed to measure the levels of glutathione in the motor cortex; levels of glutathione at Week 12 (post-treatment) will be compared to pre-treatment levels.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Five (5) subjects did not have a MRS done at the Baseline and Week 12 visits. Of the 20 that had a baseline MRS, 2 patients did not have a Week 12 MRS done. These missing MRS scans are due to technical difficulties, such as subjects were unable to complete the scan.

Arm/Group Title		Open-label
Arm/Group Description:		Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Overall Number of Participants Analyzed		20
Mean (Standard Deviation); Unit of Measure: mM
Motor Cortex Precentral Gyri (Baseline)	Number Analyzed	20 participants
		0.424 (0.064)
Motor Cortex Precentral Gyri (Week 12)	Number Analyzed	18 participants
		0.392 (0.064)

5. Secondary Outcome

Title	Blood Biomarkers (FRAP) at Baseline and Week 12
Description	Blood samples will be obtained at baseline and after 12 weeks of treatment to measure biomarkers of oxidative stress and damage such as ferric reducing antioxidant power (FRAP).
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

One (1) subject did not have blood drawn for FRAP analysis at the Baseline Visit. Four (4) subjects did not have blood drawn for FRAP analysis at the Week 12 visit. These missing samples are due to technical issues, such as a difficult blood draw or issue with sample processing.

Arm/Group Title		Open-label
Arm/Group Description:		Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Overall Number of Participants Analyzed		24
Mean (Standard Deviation); Unit of Measure: µM
Ferric Reducing Antioxidant Power (Baseline)	Number Analyzed	24 participants
		765.7 (155.1)
Ferric Reducing Antioxidant Power (Week 12)	Number Analyzed	21 participants
		1188.3 (294.1)

Adverse Events

Time Frame	Adverse events were collected from the time the subject signed consent until 28 days after a subject's last dose of study drug.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
All-Cause Mortality
	Open-label
	Affected / at Risk (%)
Total	1/25 (4.00%)
Serious Adverse Events
	Open-label
	Affected / at Risk (%)	# Events
Total	3/25 (12.00%)
Infections and infestations
Abdominal Abscess † 1	1/25 (4.00%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea † 1	1/25 (4.00%)	1
Respiratory Failure † 1	1/25 (4.00%)	1
1 Term from vocabulary, MedDRA (17.1); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Open-label
	Affected / at Risk (%)	# Events
Total	22/25 (88.00%)
Gastrointestinal disorders
Constipation † 1	2/25 (8.00%)	2
Dysphagia aggravated † 1	2/25 (8.00%)	2
General disorders
Fatigue † 1	2/25 (8.00%)	2
Weakness worsened † 1	3/25 (12.00%)	3
Injury, poisoning and procedural complications
Ankle sprain † 1	2/25 (8.00%)	2
Fall † 1	8/25 (32.00%)	11
Investigations
Weight Loss † 1	4/25 (16.00%)	4
Metabolism and nutrition disorders
Decreased appetite † 1	2/25 (8.00%)	2
Musculoskeletal and connective tissue disorders
Weakness of arms † 1	2/25 (8.00%)	2
1 Term from vocabulary, MedDRA (17.1); † Indicates events were collected by 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: Sabrina Paganoni, MD, PhD
• Organization: Massachusetts General Hospital
• Phone: 617-724-3914
• EMail: spaganoni@mgh.harvard.edu

Publications:

Paganoni S, Zhang M, Quiroz Zarate A, Jaffa M, Yu H, Cudkowicz ME, Wills AM. Uric acid levels predict survival in men with amyotrophic lateral sclerosis. J Neurol. 2012 Sep;259(9):1923-8. doi: 10.1007/s00415-012-6440-7. Epub 2012 Feb 10.

Atassi N, Berry J, Shui A, Zach N, Sherman A, Sinani E, Walker J, Katsovskiy I, Schoenfeld D, Cudkowicz M, Leitner M. The PRO-ACT database: design, initial analyses, and predictive features. Neurology. 2014 Nov 4;83(19):1719-25. doi: 10.1212/WNL.0000000000000951. Epub 2014 Oct 8.

Parkinson Study Group SURE-PD Investigators; Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, Hooper DC, Kieburtz KD, Macklin EA, Oakes D, Rudolph A, Shoulson I, Tennis MK, Espay AJ, Gartner M, Hung A, Bwala G, Lenehan R, Encarnacion E, Ainslie M, Castillo R, Togasaki D, Barles G, Friedman JH, Niles L, Carter JH, Murray M, Goetz CG, Jaglin J, Ahmed A, Russell DS, Cotto C, Goudreau JL, Russell D, Parashos SA, Ede P, Saint-Hilaire MH, Thomas CA, James R, Stacy MA, Johnson J, Gauger L, Antonelle de Marcaida J, Thurlow S, Isaacson SH, Carvajal L, Rao J, Cook M, Hope-Porche C, McClurg L, Grasso DL, Logan R, Orme C, Ross T, Brocht AF, Constantinescu R, Sharma S, Venuto C, Weber J, Eaton K. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol. 2014 Feb;71(2):141-50. doi: 10.1001/jamaneurol.2013.5528.

• Responsible Party: Sabrina Paganoni, M.D., Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02288091
• Other Study ID Numbers: 701
• First Submitted: November 5, 2014
• First Posted: November 11, 2014
• Results First Submitted: February 8, 2017
• Results First Posted: October 2, 2017
• Last Update Posted: November 6, 2017