Early Treatment of Amyotrophic Lateral Sclerosis (ALS) With Nutrition and Non-Invasive Positive Pressure Ventilation

• Sponsor: Edward Kasaraskis (Other)
• Overall Status: Completed
• CT.gov ID: NCT00116558
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 153
• Locations: 12
• Arms: 3
• Actual Duration (Months): 89
• Patients Per Site: 12.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purposes of the study are to determine the energy balance and evaluate the nutritional status of patients with ALS, and to investigate the use of NIPPV as respiratory support to treat patients with ALS.

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Device: Early NIPPV; Device: Standard NIPPV	N/A

Detailed Description

Studies to date indicate that percutaneous endoscopic gastrostomy (PEG)-insertion of a feeding tube in the stomach-and non-invasive positive pressure ventilation (NIPPV)-mechanically assisted or generated breaths delivered through a tightly fitting nasal or facial mask-improve survival in amyotrophic lateral sclerosis (ALS), even when introduced late in the disease.

Dr. Kasarskis and his research team believe early intervention with these treatments may improve patients outcome even further. However, many issues regarding the early use of these treatments prevent the design of a phase III clinical trial to test this hypothesis. Common to both NIPPV and nutrition is a lack of a reliable indicator of early respiratory or nutritional insufficiency. With respect to nutrition, reliable and cost effective methods are needed to determine a patient's energy (i.e. caloric) requirements at different stages of the illness to establish a basis for recommending PEG on the adequacy of energy intake. For NIPPV, factors that influence acceptance and tolerability of this therapy, and measurements of early respiratory dysfunction need to be identified.

The purposes of this trial are to develop and validate strategies to improve tolerability of NIPPV, identify factors that influence acceptance of NIPPV, and evaluate measures of early respiratory failure, other than percentage of forced vital capacity (FVC). Researchers will also develop and validate methods to determine energy balance in and evaluate the nutritional status of patients with ALS that will be applicable to a multi-center phase III study of nutrition and NIPPV.

The study will be conducted at 11 other sites across the country. Some study sites will focus on the nutritional aspects of the trial while the other sites will focus on NIPPV treatment. A total of 220 patients will be studied over 2 years.

Enrollment will end on June 30, 2007. The last patient was followed clinically until June 30, 2008. The study remained open for sample analysis, data analysis, and assessment of vital status until the completion of funding on November 30, 2009.

Study Design

• Study Type: Interventional
• Actual Enrollment: 153 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Early Treatment of Amyotrophic Lateral Sclerosis With Nutrition and Non-Invasive Positive Pressure Ventilation
• Actual Study Start Date: Aug 1, 2004
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early NIPPV Intervention Participants with >80% predicted forced vital capacity (FVC).	Device: Early NIPPV; Early intervention with non-invasive positive pressure ventilation (NIPPV) at 80% forced vital capacity (FVC).; Other Names: BiPAP (Bilevel Positive Airway Pressure)
Active Comparator: Standard of Care NIPPV Participants with 50-74% predicted forced vital capacity (FVC).	Device: Standard NIPPV; Standard of care non-invasive positive pressure ventilation (NIPPV) at 50% forced vital capacity (FVC).; Other Names: BiPAP (Bilevel Positive Airway Pressure)
Active Comparator: Standard of Care NIPPV and Nutritional Monitoring Participants with 50-95% forced vital capacity (FVC), and normal or impaired amyotrophic lateral sclerosis functional rating scale (ALSFRS) scores. Participants in this group will receive standard of care NIPPV therapy but will also undergo detailed analysis of nutritional status.	Device: Standard NIPPV; Standard of care non-invasive positive pressure ventilation (NIPPV) at 50% forced vital capacity (FVC).; Other Names: BiPAP (Bilevel Positive Airway Pressure)

Outcome Measures

Primary Outcome Measures

1. Acceptance Rate of Early Non-invasive Positive Pressure Ventilation (NIPPV) Treatment. [6 weeks]

   Percentage of patients attempting to use NIPPV therapy within six weeks of initial offer.

Other Outcome Measures

1. Patient Survival With Early Versus Standard of Care NIPPV Treatment [one year]

   Duration of patient survival

2. Compliance With NIPPV Treatment [one month]

   Number of hours of NIPPV use per month

3. Total Daily Energy Expediture (TDEE) of ALS Patients [Duration of study (approximately 1 year)]

   Total daily energy expenditure (TDEE) with be measured using the dual labeled water (DLW) method

4. Tolerance of NIPPV Treatment [one month]

   Percent of patients achieving tolerance (>4hr/night NIPPV after 2-3 week titration period) determined by actual usage data.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Willing and able to give informed consent.

• If women of childbearing age, must be non-lactating and surgically sterile or using an effective method of birth control (double-barrier or oral contraception) and have a negative pregnancy test.

• Minorities: All races and ethnic backgrounds.

• Disease inclusion: Clinically possible/definite/probable, or laboratory supported probable, sporadic or familial ALS according to the revised Escorial criteria.

• Onset of progressive weakness within 60 months prior to study.

• Willing to return for visits as scheduled and adhere to protocol requirements.

FVC Criteria

• NIPPV Arm: Best-sitting FVC between 50% and 95% of predicted normal.

• Nutrition Arm: Best-sitting FVC >50% of predicted normal.

Exclusion Criteria:

• Untreated or unstable hyper or hypothyroidism, untreated or unstable asthma, unstable angina, advanced liver or renal disease, advanced cancer, untreated diabetes or chronic obstructive pulmonary disease (COPD).

• Diagnosis of other motor neuron or other neurological disorder that mimics ALS.

• Diagnosis of other neurodegenerative disease (i.e., Parkinson's disease, Alzheimer's disease, etc.)

• Inflammatory bowel disease or malabsorption syndrome.

• Use of NIPPV, mechanical ventilation, or tracheostomy at the time of consent.

• Inability to adhere to study visit schedule or lack of reliable caretaker if participant requires one.

• Pregnant or lactating woman.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado	Denver	Colorado	United States	80262
2	University of Miami	Miami	Florida	United States	33136
3	University of Kentucky	Lexington	Kentucky	United States	40536
4	Henry Ford Hospital	Detroit	Michigan	United States	48202
5	Beth Israel	New York	New York	United States	10003
6	Columbia University	New York	New York	United States	10032
7	SUNY	Syracuse	New York	United States	13210
8	Pennsylvania State University	Hershey	Pennsylvania	United States	17033
9	Drexel University	Philadelphia	Pennsylvania	United States	19103
10	University of Texas-San Antonio	San Antonio	Texas	United States	78229
11	University of Utah	Salt Lake City	Utah	United States	84132
12	University of Vermont	Burlington	Vermont	United States	54505

Sponsors and Collaborators

• Edward Kasaraskis
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Edward Kasarskis, MD, PhD, University of Kentucky

Study Documents (Full-Text)

None provided.

More Information

Publications

• Kasarskis EJ, Mendiondo MS, Matthews DE, Mitsumoto H, Tandan R, Simmons Z, Bromberg MB, Kryscio RJ; ALS Nutrition/NIPPV Study Group. Estimating daily energy expenditure in individuals with amyotrophic lateral sclerosis. Am J Clin Nutr. 2014 Apr;99(4):792-803. doi: 10.3945/ajcn.113.069997. Epub 2014 Feb 12.
• Scagnelli CN, Howard DB, Bromberg MB, Kasarskis EJ, Matthews DE, Mitsumoto HM, Simmons Z, Tandan R; ALS Nutrition-NIPPV Study Group. Hydration measured by doubly labeled water in ALS and its effects on survival. Amyotroph Lateral Scler Frontotemporal Degener. 2018 May;19(3-4):220-231. doi: 10.1080/21678421.2017.1413117. Epub 2017 Dec 15.

• Responsible Party: Edward Kasaraskis, Principal Investigator, University of Kentucky
• ClinicalTrials.gov Identifier: NCT00116558
• Other Study ID Numbers: R01NS045087; R01NS045087
• First Posted: Jun 30, 2005
• Last Update Posted: Jul 31, 2019
• Last Verified: Jul 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Edward Kasaraskis, Principal Investigator, University of Kentucky: amyotrophic lateral sclerosis; ALS; Lou Gehrig's disease; nutrition; NIPPV; non-invasive positive pressure ventilation; percutaneous endoscopic gastrostomy; PEG
• Additional relevant MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis

Study Results

Participant Flow

Arm/Group Title	Standard of Care NIPPV and Nutritional Monitoring	Standard of Care NIPPV	Early NIPPV
Arm/Group Description	Participants with 50-95% forced vital capacity (FVC), and normal or impaired amyotrophic lateral sclerosis functional rating scale (ALSFRS) scores. Participants in this group will receive standard of care NIPPV therapy but will also undergo detailed analysis of nutritional status.	Participants with 50-74% predicted forced vital capacity (FVC).	Participants with >80% predicted forced vital capacity (FVC).
Period Title: Overall Study
STARTED	80	26	47
COMPLETED	49	11	14
NOT COMPLETED	31	15	33

Baseline Characteristics

Arm/Group Title	Standard of Care NIPPV and Nutritional Monitoring	Standard of Care NIPPV	Early NIPPV Intervention	Total
Arm/Group Description	Participants with 50-95% forced vital capacity (FVC), and normal or impaired amyotrophic lateral sclerosis functional rating scale (ALSFRS) scores. Participants in this group will receive standard of care NIPPV therapy but will also undergo detailed analysis of nutritional status.	Participants with 50-74% predicted forced vital capacity (FVC).	Participants with >80% predicted forced vital capacity (FVC).	Total of all reporting groups
Overall Participants	80	26	47	153
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.0 (11.7)	60.8 (11.4)	56.2 (11.2)	58.6 (11.6)
Sex: Female, Male (Count of Participants)
Female	28 35%	10 38.5%	17 36.2%	55 35.9%
Male	52 65%	16 61.5%	30 63.8%	98 64.1%
Region of Enrollment (participants) [Number]
United States	80 100%	26 100%	47 100%	153 100%

Outcome Measures

1. Primary Outcome

Title	Acceptance Rate of Early Non-invasive Positive Pressure Ventilation (NIPPV) Treatment.
Description	Percentage of patients attempting to use NIPPV therapy within six weeks of initial offer.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Data were not obtained from the "Standard of Care NIPPV and Nutritional Monitoring" arm.

Arm/Group Title	Standard of Care NIPPV and Nutritional Monitoring	Standard of Care NIPPV	Early NIPPV Intervention
Arm/Group Description	Participants with 50-95% forced vital capacity (FVC), and normal or impaired amyotrophic lateral sclerosis functional rating scale (ALSFRS) scores. Participants in this group will receive standard of care NIPPV therapy but will also undergo detailed analysis of nutritional status.	Participants with 50-74% predicted forced vital capacity (FVC).	Participants with >80% predicted forced vital capacity (FVC).
Measure Participants	0	26	47
Count of Participants [Participants]	0 0%	23 88.5%	35 74.5%

2. Other Pre-specified Outcome

Title	Patient Survival With Early Versus Standard of Care NIPPV Treatment
Description	Duration of patient survival
Time Frame	one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Other Pre-specified Outcome

Title	Compliance With NIPPV Treatment
Description	Number of hours of NIPPV use per month
Time Frame	one month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Total Daily Energy Expediture (TDEE) of ALS Patients
Description	Total daily energy expenditure (TDEE) with be measured using the dual labeled water (DLW) method
Time Frame	Duration of study (approximately 1 year)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Tolerance of NIPPV Treatment
Description	Percent of patients achieving tolerance (>4hr/night NIPPV after 2-3 week titration period) determined by actual usage data.
Time Frame	one month

Outcome Measure Data

Analysis Population Description

No data were collected for the "Standard of Care NIIPPV and Nutritional Monitoring" arm.

Arm/Group Title	Standard of Care NIPPV and Nutritional Monitoring	Standard of Care NIPPV	Early NIPPV
Arm/Group Description	Participants with 50-95% forced vital capacity (FVC), and normal or impaired amyotrophic lateral sclerosis functional rating scale (ALSFRS) scores. Participants in this group will receive standard of care NIPPV therapy but will also undergo detailed analysis of nutritional status.	Participants with 50-74% predicted forced vital capacity (FVC).	Participants with >80% predicted forced vital capacity (FVC).
Measure Participants	0	23	35
Count of Participants [Participants]	0 0%	11 42.3%	14 29.8%

Adverse Events

Time Frame	3 years, 4 months
Arm/Group Title	Combined Arms
Arm/Group Description	Sincere efforts were made to locate per arm data, but these data are no longer available. All adverse events are reported as one arm/group.
All Cause Mortality
	Combined Arms
	Affected / at Risk (%)	# Events
Total	19/153 (12.4%)
Serious Adverse Events
	Combined Arms
	Affected / at Risk (%)	# Events
Total	42/153 (27.5%)
Cardiac disorders
Cardiac Arrest	1/153 (0.7%)	1
Irregular Heartbeat	2/153 (1.3%)	2
Myocardial Infarction	1/153 (0.7%)	1
Gastrointestinal disorders
Colonic Bleed	1/153 (0.7%)	1
Dislodged PEG Tube	1/153 (0.7%)	1
Distended Abdomen	1/153 (0.7%)	1
Dysphagia	3/153 (2%)	3
PEG Procedure Complications	2/153 (1.3%)	2
Sepsis	1/153 (0.7%)	1
General disorders
Death	14/153 (9.2%)	14
Infections and infestations
Infection	2/153 (1.3%)	2
Metabolism and nutrition disorders
Failure to Thrive	1/153 (0.7%)	1
Hypokalemia, hypomagnesia, and antythmia	1/153 (0.7%)	1
Musculoskeletal and connective tissue disorders
Hip Fracture	1/153 (0.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Liver Cancer Diagnosis	1/153 (0.7%)	1
Transitional Cell Carcinoma	1/153 (0.7%)	1
Nervous system disorders
ALS Progression	1/153 (0.7%)	1
Concussion	1/153 (0.7%)	1
Renal and urinary disorders
Bladder malignancy/UTI	1/153 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	1/153 (0.7%)	1
Aspiration Pneumonia	1/153 (0.7%)	1
Blood Clot	1/153 (0.7%)	1
Difficulty Breathing	1/153 (0.7%)	1
Dyspnea	1/153 (0.7%)	1
Loculated right pleural effusion	1/153 (0.7%)	1
Pneumonia	4/153 (2.6%)	4
Pulmonary Emboli and pneumonia	1/153 (0.7%)	1
Respiratory Complications	2/153 (1.3%)	2
Respiratory Failure	2/153 (1.3%)	2
Shortness of Breath	2/153 (1.3%)	2
Skin and subcutaneous tissue disorders
Laceration	1/153 (0.7%)	1
Subarachroid Hemmorrhage and Contusion	1/153 (0.7%)	1
Subdural Hematoma	1/153 (0.7%)	1
Surgical and medical procedures
Peg Replacement	2/153 (1.3%)	2
Other (Not Including Serious) Adverse Events
	Combined Arms
	Affected / at Risk (%)	# Events
Total	62/153 (40.5%)
Blood and lymphatic system disorders
Edema	7/153 (4.6%)	7
Cardiac disorders
Hypertension	1/153 (0.7%)	1
Hypotension	1/153 (0.7%)	1
Eye disorders
Dry Eye	1/153 (0.7%)	1
Gastrointestinal disorders
Abdominal Distension	3/153 (2%)	3
Constipation	8/153 (5.2%)	8
Decreased Rectal Tone	1/153 (0.7%)	1
Dehydration	1/153 (0.7%)	1
Dental	1/153 (0.7%)	1
Diarrhea	4/153 (2.6%)	6
Diverticulitis	1/153 (0.7%)	1
Dysphagia	1/153 (0.7%)	1
Gastritis	1/153 (0.7%)	1
PEG	3/153 (2%)	3
Sialorrhea	1/153 (0.7%)	3
Stomach Upset	3/153 (2%)	3
Urgent Bowel Movements	1/153 (0.7%)	1
Vomiting	1/153 (0.7%)	1
General disorders
Burning Sensation	1/153 (0.7%)	1
Cold	7/153 (4.6%)	8
Fall	8/153 (5.2%)	9
Fatigue	5/153 (3.3%)	5
Pain	4/153 (2.6%)	6
Sore Throat	1/153 (0.7%)	2
Weight Loss	1/153 (0.7%)	1
Immune system disorders
Allergy	2/153 (1.3%)	2
Congestion	2/153 (1.3%)	2
Post Nasal Drip	2/153 (1.3%)	2
Infections and infestations
Conjunctivitis	2/153 (1.3%)	2
Ear Infection	1/153 (0.7%)	1
Infection	1/153 (0.7%)	1
Sinus Infection	1/153 (0.7%)	1
UTI	4/153 (2.6%)	5
Metabolism and nutrition disorders
Abnormal Lab	8/153 (5.2%)	8
Hypercarbia	1/153 (0.7%)	1
Musculoskeletal and connective tissue disorders
Ankle Sprain	1/153 (0.7%)	1
Arthritis	1/153 (0.7%)	1
Back Pain	4/153 (2.6%)	4
Fracture	1/153 (0.7%)	1
Knee Sprain	1/153 (0.7%)	1
Osteopenia	1/153 (0.7%)	1
Shoulder Pain	3/153 (2%)	3
Weakness	3/153 (2%)	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Polyp	1/153 (0.7%)	1
Nervous system disorders
Concussion	1/153 (0.7%)	1
Dizziness	3/153 (2%)	4
Hallucination	1/153 (0.7%)	1
Headache	2/153 (1.3%)	2
Renal and urinary disorders
Urinary Frequency	1/153 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Blood Clot	1/153 (0.7%)	1
Bronchitis	4/153 (2.6%)	4
Cough	1/153 (0.7%)	1
Nosebleed	1/153 (0.7%)	1
Pneumonia	1/153 (0.7%)	1
RADS	1/153 (0.7%)	1
Shortness of breath	2/153 (1.3%)	2
Spasm (Respiratory)	1/153 (0.7%)	1
Wheezing	1/153 (0.7%)	1
Skin and subcutaneous tissue disorders
Blister	1/153 (0.7%)	1
Bruise	2/153 (1.3%)	2
Contusion	1/153 (0.7%)	1
Dermatitis	1/153 (0.7%)	1
Laceration	2/153 (1.3%)	3
Lesion	1/153 (0.7%)	1
Pressure Sores	1/153 (0.7%)	2
Rash	4/153 (2.6%)	4

Limitations/Caveats

Compliance with NIPPV intervention is limited due to technical difficulties in obtaining BiPAP download data from some sites. This was due to variability in the local respiratory therapists engaged by commercial respiratory therapy companies.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.