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出境医 / 临床实验 / Investigation of Supplemental L-alanine in the Management of Dietary Fructose Intolerance

Investigation of Supplemental L-alanine in the Management of Dietary Fructose Intolerance

Study Description
Brief Summary:

Over the past few decades, fructose consumption has risen significantly in the United States1. This sugar is increasingly being used as a sweetener in a variety of foods1. Because there is a limited absorptive capacity for fructose, excessive ingestion of fructose leads to fructose malabsorption and dietary fructose intolerance (DFI) 2-9, 13. Incomplete absorption of fructose may lead to a variety of gastrointestinal symptoms, including bloating, pain, gas and diarrhea 2-9. In tertiary care centers, the prevalence of DFI in subjects with unexplained GI symptoms has been estimated to range between 11-50 %, when subjects were assessed with breath tests following administration of 25 grams of fructose 2, 5-7.

Currently, the main treatment for DFI consists of restricting the intake of fructose-containing foods 10-12 or limiting the intake of foods with excess "free fructose" (ie, fructose in excess of glucose) or a high fructan content17. These diet restrictions can improve symptoms in patients with DFI 10-12,17. However, the diet is very restrictive and imposes a significant burden on the individual and the family. In one study, 40% of subjects were unable to comply with dietary restrictions 10. Currently, there are no other therapeutic agents for treating this condition 14, 15. Apart from promoting intestinal fructose absorption, an ideal therapeutic agent should be safe, simple to use, inexpensive and have no calorific value.

Fructose is mostly absorbed in the small intestine by facilitated diffusion which is mediated by the GLUT-5 transporter protein. This protein is expressed on the intestinal mucosal surface. In the presence of glucose, fructose absorption is increased, mostly due to co-transport with glucose via the GLUT-2 transporter protein. However, the calorie content of glucose precludes its routine use in patients with DFI. Other compounds that promote fructose absorption, such as 3 O-methyl glucose and epidermal growth factor (EGF) have significant side effects and safety issues, making them unsuitable for clinical use in DFI.

Several amino acids, including alanine, have been also been shown to increase intestinal fructose absorption 14. The postulated mechanism is as follows: transmucosal Na+-coupled amino acid transport causes increased water flow through the mucosal apical membrane14. This, in turn, facilitates fructose absorption by a process of 'solvent drag', caused by an increase in intraluminal fructose concentration caused by water removal from the lumen14. The potential benefit of alanine was assessed in a European study in healthy children 14. Ten subjects underwent H2 breath tests following administration of fructose alone (2g/ Kg body weight), followed by a combination of fructose and an equi-molar dose of various amino acids (L-alanine, L-phenylalanine, L-glutamine, L-proline) or glucose. Breath H2 production was assessed as a marker of intestinal fructose absorption. Subjects were asked to report any gastrointestinal symptoms during the test. All subjects had a positive (>20 ppm of H2) breath test (68 ± 38 ppm) with fructose and 6/10 subjects reported either abdominal pain or diarrhea during the test. Co-administration of alanine caused a significant (p < 0.05) decrease in breath H2 production (3 ± 3 ppm), suggesting increased intestinal fructose absorption. Furthermore, none of the subjects reported any gastrointestinal symptoms during the test.


Condition or disease Intervention/treatment Phase
Fructose Intolerance Dietary Supplement: Placedo Dietary Supplement: Alanine Not Applicable

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Investigation of Supplemental L-alanine in the Management of Dietary Fructose Intolerance: a Double-blind, Randomized Study
Actual Study Start Date : January 7, 2014
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : December 30, 2020
Arms and Interventions
Arm Intervention/treatment
Placebo Comparator: Placebo

Psyllium powder is used as the placebo. A member of the research staff will package and dispense L-alanine and placebo in similar containers. A standard measuring spoon will be provided to the subject for preparing the placebo solution. Subjects will mix the placebo in the beverage of their choice and consume this approximately 20 minutes before meals or snacks, in according with the dosing guidelines set for them by the dietitian.

Meal Placebo Breakfast * 1-2 scoops Snack * .5 - 1 scoop Lunch * 1-2 scoops Snack * .5 - 1 scoop Dinner * 1-2 scoops

Dietary Supplement: Placedo
Subjects will mix the placebo in the beverage of their choice and consume this approximately 20 minutes before meals or snacks, in according with the dosing guidelines set for them by the dietitian.

Experimental: Experimental Alanine

L-alanine, USP (Spectrum® Chemicals and Laboratory Products, Gardena, CA) will be packaged and dispensed by one member of the research staff who will have no other role in the study. A one-month supply will be dispensed to the subjects.

Meal L-Alanine Breakfast * 1-2 scoops Snack * .5 - 1 scoop Lunch * 1-2 scoops Snack * .5 - 1 scoop Dinner * 1-2 scoops

Dietary Supplement: Alanine
Subjects will mix the alanine in the beverage of their choice and consume this approximately 20 minutes before meals or snacks, in according with the dosing guidelines set for them by the dietitian.

Outcome Measures
Primary Outcome Measures :
  1. GI symptom score [ Time Frame: 4 weeks ]
    Change in GI symptom score with alanine and placebo, when compared to the baseline


Secondary Outcome Measures :
  1. Fructose consumption [ Time Frame: 4 weeks ]
    Estimated daily consumption of fructose during the alanine and placebo phases, when compared to the baseline using prospective food diaries

  2. Breath hydrogen and methane [ Time Frame: 4 weeks ]
    Changes in breath hydrogen and/or methane values with alanine and placebo when compared with to the baseline

  3. Quality of Life (SF-12) [ Time Frame: 4 weeks ]
    Changes in SF-12 scores between and after baseline and placebo


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of fructose malabsorption (positive breath test after ingestion of 25 grams of fructose defined as either (a) ≥ 20 ppm rise of breath H2/CH4/both over baseline values or a successive rise of ≥ 5 ppm over baseline and in 3 consecutive breath samples)
  • Women of childbearing potential must agree to a urine pregnancy test before supplement is dispensed and to avoid pregnancy throughout the study.

Exclusion Criteria:

  • Cognitive impairment or any other inability to provide informed consent
  • Prisoners
  • GI surgery except appendectomy, cholecystectomy, caesarean section, hysterectomy
  • Antibiotics in the previous 6 weeks.
  • Major co-morbid illnesses, including chronic pancreatitis, celiac disease, inflammatory bowel disease, diabetes, scleroderma, pseudo-obstruction syndromes etc.
  • Medication use: opioids, Tegaserod, laxatives, enemas
  • Difficulty Swallowing
  • Known food allergies or intolerance to any fiber supplements or other dietary nutritional supplements such as: Psyllium (Metamucil), Maltodextrin, Citric Acid, and methylcellulose (Citrucel).
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Satish Rao, MD 7067211968 srao@augusta.edu
Contact: Helen Smith 7067211968 hsmith@augusta.edu

Locations
Layout table for location information
United States, Georgia
Augusta University Recruiting
Augusta, Georgia, United States, 30912
Contact: Satish Rao, MD    706-721-1968    srao@augusta.edu   
Contact: Helen Smith    7067211968    hsmith@augusta.edu   
Sponsors and Collaborators
Augusta University
Tracking Information
First Submitted Date  ICMJE July 15, 2019
First Posted Date  ICMJE July 17, 2019
Last Update Posted Date April 15, 2020
Actual Study Start Date  ICMJE January 7, 2014
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 13, 2020)
GI symptom score [ Time Frame: 4 weeks ]
Change in GI symptom score with alanine and placebo, when compared to the baseline
Original Primary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
Decrease breath Hydrogen and/or Methane production [ Time Frame: less than 6 months ]
Breath test
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 13, 2020)
  • Fructose consumption [ Time Frame: 4 weeks ]
    Estimated daily consumption of fructose during the alanine and placebo phases, when compared to the baseline using prospective food diaries
  • Breath hydrogen and methane [ Time Frame: 4 weeks ]
    Changes in breath hydrogen and/or methane values with alanine and placebo when compared with to the baseline
  • Quality of Life (SF-12) [ Time Frame: 4 weeks ]
    Changes in SF-12 scores between and after baseline and placebo
Original Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
Occurrence or severity of GI symptoms during the test [ Time Frame: less than 6 months ]
GI symptoms questionnaire
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Investigation of Supplemental L-alanine in the Management of Dietary Fructose Intolerance
Official Title  ICMJE Investigation of Supplemental L-alanine in the Management of Dietary Fructose Intolerance: a Double-blind, Randomized Study
Brief Summary

Over the past few decades, fructose consumption has risen significantly in the United States1. This sugar is increasingly being used as a sweetener in a variety of foods1. Because there is a limited absorptive capacity for fructose, excessive ingestion of fructose leads to fructose malabsorption and dietary fructose intolerance (DFI) 2-9, 13. Incomplete absorption of fructose may lead to a variety of gastrointestinal symptoms, including bloating, pain, gas and diarrhea 2-9. In tertiary care centers, the prevalence of DFI in subjects with unexplained GI symptoms has been estimated to range between 11-50 %, when subjects were assessed with breath tests following administration of 25 grams of fructose 2, 5-7.

Currently, the main treatment for DFI consists of restricting the intake of fructose-containing foods 10-12 or limiting the intake of foods with excess "free fructose" (ie, fructose in excess of glucose) or a high fructan content17. These diet restrictions can improve symptoms in patients with DFI 10-12,17. However, the diet is very restrictive and imposes a significant burden on the individual and the family. In one study, 40% of subjects were unable to comply with dietary restrictions 10. Currently, there are no other therapeutic agents for treating this condition 14, 15. Apart from promoting intestinal fructose absorption, an ideal therapeutic agent should be safe, simple to use, inexpensive and have no calorific value.

Fructose is mostly absorbed in the small intestine by facilitated diffusion which is mediated by the GLUT-5 transporter protein. This protein is expressed on the intestinal mucosal surface. In the presence of glucose, fructose absorption is increased, mostly due to co-transport with glucose via the GLUT-2 transporter protein. However, the calorie content of glucose precludes its routine use in patients with DFI. Other compounds that promote fructose absorption, such as 3 O-methyl glucose and epidermal growth factor (EGF) have significant side effects and safety issues, making them unsuitable for clinical use in DFI.

Several amino acids, including alanine, have been also been shown to increase intestinal fructose absorption 14. The postulated mechanism is as follows: transmucosal Na+-coupled amino acid transport causes increased water flow through the mucosal apical membrane14. This, in turn, facilitates fructose absorption by a process of 'solvent drag', caused by an increase in intraluminal fructose concentration caused by water removal from the lumen14. The potential benefit of alanine was assessed in a European study in healthy children 14. Ten subjects underwent H2 breath tests following administration of fructose alone (2g/ Kg body weight), followed by a combination of fructose and an equi-molar dose of various amino acids (L-alanine, L-phenylalanine, L-glutamine, L-proline) or glucose. Breath H2 production was assessed as a marker of intestinal fructose absorption. Subjects were asked to report any gastrointestinal symptoms during the test. All subjects had a positive (>20 ppm of H2) breath test (68 ± 38 ppm) with fructose and 6/10 subjects reported either abdominal pain or diarrhea during the test. Co-administration of alanine caused a significant (p < 0.05) decrease in breath H2 production (3 ± 3 ppm), suggesting increased intestinal fructose absorption. Furthermore, none of the subjects reported any gastrointestinal symptoms during the test.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Fructose Intolerance
Intervention  ICMJE
  • Dietary Supplement: Placedo
    Subjects will mix the placebo in the beverage of their choice and consume this approximately 20 minutes before meals or snacks, in according with the dosing guidelines set for them by the dietitian.
  • Dietary Supplement: Alanine
    Subjects will mix the alanine in the beverage of their choice and consume this approximately 20 minutes before meals or snacks, in according with the dosing guidelines set for them by the dietitian.
Study Arms  ICMJE
  • Placebo Comparator: Placebo

    Psyllium powder is used as the placebo. A member of the research staff will package and dispense L-alanine and placebo in similar containers. A standard measuring spoon will be provided to the subject for preparing the placebo solution. Subjects will mix the placebo in the beverage of their choice and consume this approximately 20 minutes before meals or snacks, in according with the dosing guidelines set for them by the dietitian.

    Meal Placebo Breakfast * 1-2 scoops Snack * .5 - 1 scoop Lunch * 1-2 scoops Snack * .5 - 1 scoop Dinner * 1-2 scoops

    Intervention: Dietary Supplement: Placedo
  • Experimental: Experimental Alanine

    L-alanine, USP (Spectrum® Chemicals and Laboratory Products, Gardena, CA) will be packaged and dispensed by one member of the research staff who will have no other role in the study. A one-month supply will be dispensed to the subjects.

    Meal L-Alanine Breakfast * 1-2 scoops Snack * .5 - 1 scoop Lunch * 1-2 scoops Snack * .5 - 1 scoop Dinner * 1-2 scoops

    Intervention: Dietary Supplement: Alanine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 15, 2019)
65
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2020
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of fructose malabsorption (positive breath test after ingestion of 25 grams of fructose defined as either (a) ≥ 20 ppm rise of breath H2/CH4/both over baseline values or a successive rise of ≥ 5 ppm over baseline and in 3 consecutive breath samples)
  • Women of childbearing potential must agree to a urine pregnancy test before supplement is dispensed and to avoid pregnancy throughout the study.

Exclusion Criteria:

  • Cognitive impairment or any other inability to provide informed consent
  • Prisoners
  • GI surgery except appendectomy, cholecystectomy, caesarean section, hysterectomy
  • Antibiotics in the previous 6 weeks.
  • Major co-morbid illnesses, including chronic pancreatitis, celiac disease, inflammatory bowel disease, diabetes, scleroderma, pseudo-obstruction syndromes etc.
  • Medication use: opioids, Tegaserod, laxatives, enemas
  • Difficulty Swallowing
  • Known food allergies or intolerance to any fiber supplements or other dietary nutritional supplements such as: Psyllium (Metamucil), Maltodextrin, Citric Acid, and methylcellulose (Citrucel).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Satish Rao, MD 7067211968 srao@augusta.edu
Contact: Helen Smith 7067211968 hsmith@augusta.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04022434
Other Study ID Numbers  ICMJE 611777
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Augusta University
Study Sponsor  ICMJE Augusta University
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Augusta University
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP