The Fructose and Allulose Catalytic Effects (FACE) Trial

Study Overview
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Brief Summary
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Diabetes remains one of the most important unmet prevention and treatment challenges, and the prevalence of diabetes continues to grow. Some functional food ingredients may hold promise as potential therapies for diabetes. One such functional food is allulose, which is a c-3 epimer of fructose. Allulose is a non-caloric sugar found naturally in small amounts in foods such as dried fruits, brown sugar and maple syrup. Previous research has found that catalytic doses of fructose and allulose have been shown to decrease the postprandial glycemic responses to high glycemic index meals. Fructose, in exchange for other carbohydrates, has also been found to decrease HbA1c levels. Whether the effects of fructose and allulose are equivalent is of particular interest, as allulose represents a non-caloric alternative to fructose. The minimum 'catalytic' dose at which improvements in carbohydrate metabolism are observed also remains to be determined for each of the sugars in people with and without diabetes. This study is an acute randomized controlled dose-finding equivalence trial to assess the effect of fructose and allulose at 2 dose levels (5g and 10g) compared with control (0g) on the glucose and insulin responses to a 75g oral glucose tolerance test (OGTT) in healthy and type 2 diabetes participants.

Detailed Description
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Diabetes remains one of the most important unmet prevention and treatment challenges. Despite the growing armamentarium of medications, which include six new classes of drugs since metformin was first approved in 1995 in the US, the combined prevalence of impaired glucose tolerance (IGT) and diabetes continues to grow. Although oral antihyperglycaemic agents have been shown to prevent the development of diabetes in high-risk individuals and to reduce the risk of microvascular complications in individuals with type 2 diabetes, they have failed to deliver the anticipated macrovascular benefits. Some functional food ingredients may hold promise as potential therapies for diabetes. An emerging literature has shown that low-dose fructose and its c-3 epimer, allulose (a non-caloric sugar found naturally in small amounts in foods such as dried fruits, brown sugar, and maple syrup which is generally recognized as safe [GRAS] by the FDA under GRN 400 since 2012 and GRN 498 since 2014) may benefit glycemic control. Clinical translation of these findings has proven promising. Catalytic doses of fructose at 7.5g and 10g and allulose at 5g, 7.5g, and 10g (but not 2.5g) have been shown to decrease the postprandial glycemic responses to high glycemic index meals (oral glucose, maltodextrins, or mashed potatoes) from  15-30% in healthy participants and those with prediabetes or diabetes. These acute effects have been shown to be sustainable over the longer term in the case of fructose. In separate systematic reviews and meta-analyses of controlled feeding trials, the investigators showed that both small doses (defined as ≤36g/day based on 3 meals at ≤10g/meal and 2 snacks at ≤3g/snack) and higher doses (median, 60g/day) of fructose in exchange for other carbohydrates decreased HbA1c by 0.4% and 0.53%, respectively, a level of reduction which exceed the clinically meaningful threshold of 0.3% proposed by the Federal Drug Administration (FDA) for the development of new oral anti-hyperglycemic agents. Although these findings provide a compelling proof of concept, there is an urgent need for replication studies. Whether the effects of fructose and allulose are equivalent is of particular interest, as allulose represents a non-caloric alternative to fructose. The minimum 'catalytic' dose at which improvements in carbohydrate metabolism are observed also remains to be determined for each of the sugars in people with and without diabetes. OBJECTIVES To assess the acute catalytic effects of fructose and allulose at 2 dose levels (5g, 10g) compared with control (0g) on glucose and insulin responses to a 75g oral glucose tolerance test (75g-OGTT) in healthy participants and participants with type 2 diabetes. To assess whether there is a dose response or threshold over the proposed dose range (0g, 5g, 10g) for the effects of fructose and allulose on glucose and insulin responses to a 75g-OGTT in healthy participants and participants with type 2 diabetes. To assess whether the effects of allulose and fructose are equivalent on the primary endpoint of incremental area under the curve (iAUC) for plasma glucose across the 2 dose levels (5g and 10g) compared with control (0g) in healthy participants and participants with type 2 diabetes.

Official Title
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An Acute Randomized Dose-finding Equivalence Trial of Small, Catalytic Doses of Fructose and Allulose on Postprandial Carbohydrate Metabolism: The Fructose and Allulose Catalytic Effects (FACE) Study

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Other: Allulose
* Other: Fructose
* Other: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy participants: Adult males and non-pregnant females Normal weight Non-smokers Free of any disease or illness Do not regular take any medications Have a primary care physician Diabetes participants: Well-controlled diabetes on diet and/or oral antihyperglycemic agents Not taking insulin Free of any major illness Have a primary care physician Exclusion Criteria: Healthy participants: Age <18 or >75y, Pregnant female Regular medication use Complementary or alternative medicine (CAM) use BMI<18.5kg/m2, >30kg/m2 Prediabetes or diabetes (HbA1c≥6%, FBG≥6.1mmol/L) Hypertension (BP≥140/90), Dyslipidemia (Canadian Cardiovascular Society guidelines) Metabolic syndrome (harmonized definition) Polycystic ovarian syndrome Cardiovascular disease Gastrointestinal disease Previous bariatric surgery Liver disease (abnormal liver enzymes) Hyperthyroidism (abnormal TSH) Hypothyroidism (abnormal TSH) Nephropathy (albumin-to-creatinine ratio [ACR] >20) Chronic kidney disease (eGFR >60ml/min/1.73m2) Inflammatory conditions (CRP>3g/L) Acute or chronic infection (abnormal white blood cell count (WBC), CRP>3g/L) Anemia (abnormal Hb) Lung disease Cancer/malignancy Psychiatric illness Major surgery in the last 6 months Other major illness Smoker Heavy alcohol use (>3 drinks/day) Diabetes participants: Age <18 or >75y Pregnant female Poorly controlled diabetes (HbA1c>7.5%) Recent diabetes medication change (< 3 months) Insulin use Complementary or alternative medicine (CAM) use BMI<18.5kg/m2, ≥35kg/m2 Cardiovascular disease Retinopathy Neuropathy Diabetic foot Gastrointestinal disease Previous bariatric surgery Liver disease (abnormal liver enzymes) Hyperthyroidism (abnormal TSH) Hypothyroidism (abnormal TSH) Anemia (abnormal Hb) Nephropathy (albumin-to-creatinine ratio [ACR] >20) Chronic kidney disease (eGFR >60ml/min/1.73m2) Inflammatory conditions (CRP>3g/L) Acute or chronic infection (abnormal WBC, CRP>3g/L) Lung disease Cancer/malignancy Psychiatric illness Major surgery in the last 6 months Other major illness Smoker Heavy alcohol use (>3 drinks/day)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allulose + 75g OGTT<br>Allulose added to a 75 g OGTT of 500 mL at 2 doses (5g and 10g). The drinks will be matched as much as possible in appearance, taste (sweetness), texture, and packaging. | Other: Allulose<br>* A double-blind, randomized, multiple-crossover equivalence design. Each participant will act as their own control receiving the treatments in random order, each separated by a 1 week washout period. The treatment will be developed by Tate & Lyle.<br>* Other names: D-psicose;|
| Experimental: Fructose + 75g OGTT<br>Fructose added to a 75 g OGTT of 500 mL at 2 doses (5g and 10g). The drinks will be matched as much as possible in appearance, taste (sweetness), texture, and packaging. | Other: Fructose<br>* A double-blind, randomized, multiple-crossover equivalence design. Each participant will act as their own control receiving the treatments in random order, each separated by a 1 week washout period. The treatment will be developed by Tate & Lyle.<br>|
| Active Comparator: 75g OGTT (Control)<br>A 75 g OGTT (alone) of 500 mL will be given to each participant. The drinks will be matched as much as possible in appearance, taste (sweetness), texture, and packaging. | Other: Control<br>* A double-blind, randomized, multiple-crossover equivalence design. Each participant will act as their own control receiving the treatments in random order, each separated by a 1 week washout period. The treatment will be developed by Tate & Lyle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma glucose iAUC |  | up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma glucose total AUC |  | up to 12 weeks | 
| Plasma insulin iAUC |  | up to 12 weeks | 
| Plasma insulin total AUC |  | up to 12 weeks | 
| Maximum concentrations (Cmax) for plasma glucose and insulin |  | up to 12 weeks | 
| Time of maximum concentrations (Tmax) for plasma glucose and insulin |  | up to 12 weeks | 
| Matsuda whole body insulin sensitivity index (Matsuda ISI OGTT); |  | up to 12 weeks | 
| Early insulin secretion index (∆PI30-0/∆PG30-0); |  | up to 12 weeks | 
| Insulin secretion-sensitivity index-2 (ISSI-2) |  | up to 12 weeks | 
| Mean incremental plasma glucose and insulin responses |  | up to 12 weeks | 
| Mean plasma glucose and insulin responses |  | up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fructose, Allulose, Dose Response, Catalytic Dose, Carbohydrate metabolism, Randomized clinical trials