Oral Ketones and Exercise Among Patients With Long-chain Fatty Acid Oxidation Disorders

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to determine if an oral ketone beverage is safe and well-tolerated during moderate intensity exercise in participants with long-chain fatty acid oxidation disorders and if it will raise blood ketones to levels similar to that reported among normal healthy subjects.

Detailed Description
-----------------
Purpose: Subjects with long-chain fatty acid oxidation disorders (LC-FAOD) do not make ketones during fasting or with exercise. Ketones are an important alternative energy substrate during moderate exercise, sparing the oxidation of glucose and providing a source of ATP to the central nervous system and exercising muscle. Fatty acid oxidation in the liver is required to make ketones. Subjects with a LC-FAOD cannot generate ketones because of their block in fatty acid oxidation during exercise. Providing ketones in an oral ketone beverage may increase blood ketones with exercise to levels normally observed in humans. Aim: To determine the safety and tolerability of an oral ketone beverage during moderate intensity exercise among subjects with a LC-FAOD compared to an isocaloric maltodextrin beverage, and to determine blood ketone concentrations. Hypothesis: Oral consumption of a ketone beverage before moderate intensity exercise will be safe and well-tolerated, and will raise blood ketones among subjects with a LC-FAOD to concentrations similar to that reported in the literature among normal healthy subjects.

Official Title
-----------------
Safety and Tolerability of Oral Ketones and Exercise Among Patients With Long-chain Fatty Acid Oxidation Disorders

Conditions
-----------------
Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency, Carnitine Palmitoyltransferase Deficiency 2, Very Long Chain Acyl Coa Dehydrogenase Deficiency, Trifunctional Protein Deficiency

Intervention / Treatment
-----------------
* Dietary Supplement: Nutritional Ketone Supplement
* Dietary Supplement: Isocaloric Placebo Supplement


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: confirmed diagnosis of VLCAD, LCHAD/TFP or CPT2 deficiency speak English willing to complete 2 moderate intensity exercise treadmills Exclusion Criteria: subjects actively participating in another research study that prohibits their participation pregnant females subjects with diabetes or taking medications to treat diabetes

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Subjects with either CPT2, TFP, LCHAD or VLCAD deficiency will be randomized to receive a ketone beverage (see composition in Appendix A) or an isocaloric maltodextrin control beverage (see composition in Appendix A) before moderate intensity exercise. Twenty minutes after consuming the pre-exercise beverage, subjects will complete a moderate intensity treadmill exercise test for 45 minutes. After a washout period of 48 hours, subjects will repeat the exercise. During the 2nd exercise test subjects will crossover to the beverage not consumed during the 1st exercise study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nutrition Ketogenic Supplement<br>The Ketone pre-exercise beverage is a nutritional supplement. The supplement will be provided by Nestle as powered sachets to mix in water. It contains a mix of D-beta-hydroxybutyrate salts, flavors and stevia. | Dietary Supplement: Nutritional Ketone Supplement<br>* Mix of sodium, calcium, and magnesium salts of D-beta-hydroxybutyrate with nicotinamide riboside chloride, flavors and stevia sweetener<br>* Other names: NKS;|
| Sham Comparator: Isocaloric Placebo Supplement<br>The maltodextrin pre-exercise beverage is a nutritional supplement. The supplement will be provided by Nestle as powered sachets to mix in water. It contains an isocaloric amount of maltodextrin, flavors and stevia similar to the ketone beverage. | Dietary Supplement: Isocaloric Placebo Supplement<br>* Maltodextrin with flavors and stevia sweetener<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events- incidence | Number of Adverse events | 2 hours after product intake | 
| Adverse Events- type | Description of Adverse events: categorical | 2 hours after product intake | 
| Adverse Events- severity | Severity of adverse event: grade 1-5 | 2 hours after product intake | 
| Adverse Events- causal relationship | Yes/No related to product intake | 2 hours after product intake | 
| Abdominal discomfort | visual analogue scale (VAS) 0-10 | 2 hours after product intake | 
| Decreased appetite | visual analogue scale (VAS) 0-10 | 2 hours after product intake | 
| Gastric reflux | visual analogue scale (VAS) 0-10 | 2 hours after product intake | 
| Nausea | visual analogue scale (VAS) 0-10 | 2 hours after product intake | 
| Diarrhea | visual analogue scale (VAS) 0-10 | 2 hours after product intake | 
| Headache | visual analogue scale (VAS) 0-10 | 2 hours after product intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Ketones | plasma beta-hydroxybutyrate concentration | 20 minutes after moderate intensity exercise | 
| Blood Creatine Kinase | plasma CK concentration | 20 minutes after moderate intensity exercise | 
| Blood Glucose | serum glucose | 20 minutes after moderate intensity exercise | 
| Blood Lactate | serum lactate concentration | 20 minutes after moderate intensity exercise | 
| Blood Pressure | diastolic BP | peak 40 minute exercise | 
| Blood Pressure | systolic BP | peak 40 minute exercise | 
| Perceived exertion | Borg scale 1-20 | peak 40 minute exercise | 
| Respiratory Exchange Ratio | VCO2/VO2 0.7 - 1.0 | peak 40 minute exercise | 
| Heart Rate | beats per minute | peak 40 minute exercise |