Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06185790 |
| Other study ID # |
NL85039.091.23 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 5, 2024 |
| Est. completion date |
December 31, 2024 |
Study information
| Verified date |
November 2023 |
| Source |
Radboud University Medical Center |
| Contact |
Heidi Zweers- van Essen, Doctor |
| Phone |
+31625067451 |
| Email |
Heidi.Zweers-vanEssen[@]radboudumc.nl |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In daily practice, doctors and dietitians in the clinic receive many questions in general
from patients with a Mitochondrial Disease (MD), and more specific whether nutritional
changes can alleviate their symptoms. Mitochondrial Inherited Diabetes and Deafness (MIDD) is
due to a mitochondrial mutation at the m.3243A>G locus. Nutrition is known to affect disease
burden in MIDD. Which diet does this best is unknown. Very low carbohydrate high fat diets
improve mitochondrial function in isolated cells and in mice. Whether it does so in people
with MIDD is unknown. Therefore, the objective of the study is to explore the effect of a low
carbohydrate- high fat diet (LCHF) on clinical symptoms (Goal Attainment Scaling) and gut
microbiome in patients with MIDD due to the m.3243A>G mutation. A total of 20 adult patients
with the above mentioned characteristics will be randomized to receive first usual care
during three months (control period), followed by LCHF dietary intervention for the next
three months (intervention period), or vice versa.
Description:
Mitochondrial disease (MD) is a clinically and genetically heterogenous group of disorders.
The dysfunction of the mitochondrial respiratory chain results in ATP shortage and energy
depletion resulting in multi system disease. Therapeutic interventions are currently limited
and focus on relieving symptoms, since no curative therapies exist. The m.3243A>G related MD
is presumably the most frequent MD affecting at least 1 in 5000 people, and the MIDD
(Mitochondrial Inherited Diabetes and Deafness) phenotype is its most frequent clinical
phenotype. The role of nutrition, providing the essential nutrients for mitochondria to
produce energy, is an important disease modifier in MIDD.
A ketogenic diet (KD) is a very low-carbohydrate ( ±20 grams a day) high-fat diet that shifts
metabolism towards β-oxidation and ketone body production. In cell studies and mice models
for MD, ketone bodies or KD significantly affect different dimensions of mitochondrial
function. KD has been proven to effectively treat intractable epilepsy in children with MD.
The investigators recently performed a 12 week pilot study with KD in 20 adults with
different types of mtDNA related MD. The KD improved glucose tolerance, yielded less
migraine, and alleviated gastrointestinal symptoms. Despite these positive effects, it proved
the KD is a difficult diet to follow and only 8/20 participants finished the 12 week KD
intervention. The individuals with m.3243A>G related MD had the longest diet adherence.
Because of the positive effects, over half of all participants switched to the more feasible
and less restrictive low carbohydrate (± 50-100 gram/dag), high fat (LCHF) diet after
completing the study. The positive effect of KD on the subtype of m.3243A>G related MD was
very recently confirmed in another study. The LCHF diet however provides no ketone bodies and
its effect in mitochondrial disease is not studied properly yet.
In irritable bowel syndrome, specific dietary regimens as low-fermentable, oligo-, di-,
monosaccharides and polyols (FODMAPs) but also LCHF diets are considered therapeutic. A diet
low in fermentable carbohydrates reduces the fermentation by the gut microbiota and is
therefore thought to reduce bloating and other gastro intestinal complaints. Based on the
results of a previous study from the investigators and the effect of LCHF diets in irritable
bowel syndrome, the investigators hypothesize the same positive effect in the cohort of
m.3243A>G related MD in which gastro intestinal complaints are very common.
An adult diabetes team studied the gut microbiome and observed significant differences in
various species and pathways between the faecal stool samples of diabetes patients and
healthy controls, and that gut microbiome composition is associated with glycemic control.
The gut microbiome is a very promising study field. More insight in patients gut microbiome
and the way it can be altered with nutrition could lead to new treatment options and symptom
relieve which is very relevant to MD patients. Therefore it is interesting to compare the gut
microbiome of MIDD patients with already analysed stool samples of healthy controls and
diabetes patients, and study the effect of an LCHF diet intervention.
The LCHF diet is an established treatment option in diabetes, with positive effects on
glucose homeostasis. The investigators have initially chosen the subgroup of m.3243A>G
related MIDD patients as they hypothesize that the LCHF could help slow down the progression
of diabetes severity and reduce the necessity for treatment with insulin in these patients in
particular. Since the team could not find enough participants with MIDD they intent to
include also participants with MD caused by the m3243A>G mutation but without diabetes. These
patients still have a lot of gastro intestinal problems as well as fatigue and headaches, all
relevant symptoms that possibly can be affected with the low carbohydrate diet. So the
primary outcomes as mentions in the title of the study: effect on clinical symptoms and the
gut microbiome are relevant for this patient population aswell.
Studies in the heterogeneous patient population with MD are challenging. By choosing a
relatively frequent genotype the investigators can minimize this problem and study a defined
cohort. Additionally the investigators will use a cross over design ("patients being their
own controls") to further decrease the number of patients needed to be included to achieve
robust data.
Previous experience with trials in MD including patient consultations has led to an insight
that the Goal Attainment Scaling (GAS) is an important individually tailored outcome for this
patient group. With the GAS patients choose and score personal goals that they want to
achieve with the diet intervention.
Taken together, The investigators intend to perform a pilot study to investigate the effect
on clinical symptoms, as measured by GAS, as well as assessing gastrointestinal complaints
and the impact on the gut microbiome of a low carbohydrate, high fat diet intervention. This
study will focus on a cohort comprising adult patients exhibiting m.3234A>G mutation-related
MD. Additionally, within the subgroup of patients with m.3234A>G-related MIDD, diabetes
control will be also be evaluated.
1.1 Visits:
Visit baseline:
- Signing informed consent
- Final check inclusion and exclusion criteria
- Randomisation
- Secure baseline stool sample
- Check baseline food diary
- Vitals including blood pressure
- NMDAS , SF 12,
- GAS (Goal Attainment Scaling)
- Nutritional assessment: Weight, body composition (Multi frequency BIA SECA BCM 555)
- Online Questionnaires will be filled in Castor database during the visit under
supervision of the researcher to prevent missing data. Questionaires include: Gastro
intestinal complaints, + SF 12, CIS fatigue, diet tolerance, adverse effects and
medication
- Laboratory examinations (CK, HBA1c, lipid profile, kidney function, transaminases,
lactate, ketone bodies, metabolomics)
- Patient instructions on home measurements and if randomised in the intervention group
diet instructions including safety instructions.
Visit 12 weeks:
- NMDAS with SF 12
- Vitals including blood pressure
- GAS (Goal Attainment scaling)
- Nutritional assessment: Weight, body composition (Multi frequency BIA SECA BCM 555).
- Online Questionnaires will be filled in Castor during the visit under supervision of the
researcher to prevent missing data.
- Laboratory examinations (CK, HBA1c, lipid profile, kidney function, transaminases,
lactate, ketone bodies, metabolomics)
- Check on the home measurements and if randomised in the control group diet instructions
and if randomised in the intervention group instructions how to stop the diet.
Visit 24 weeks:
- NMDAS with SF 12
- Vitals including blood pressure
- GAS (Goal Attainment scaling)
- Nutritional assessment: Weight, body composition (Multi frequency BIA SECA BCM 555).
- Online Questionnaires will be filled in Castor during the visit under supervision of the
researcher to prevent missing data.
- Laboratory examinations (CK, HBA1c, lipid profile, kidney function, transaminases,
lactate, ketone bodies, metabolomics)
- Check on the home measurements and diet instructions for after the study based on
patients wishes.
1.2 Home measurements:
- Diet adherence will be checked with a digital food diary 3 of days including one weekend
day. At baseline, 11 weeks and 23 weeks.
- Fecal sampling at baseline, 12 weeks and 24 weeks.
- Accelerometery: Activ8® has to be worn on the upper leg for 1 week at the time: At
baseline, 11 weeks and 23 weeks.
- Weight measurement once a week.
- Headache diary: Headaches need to be registered during the whole study
- Glucose monitoring will be done with sensor derived glucometrics at the last 10 days of
both the intervention and the control period. Two times (20 days) in total. Exclusively
conducted for MIDD patients. In MIDD patients without continuous glucose monitoring in
the usual care (this are the patients without intensive insulin therapy) the sensor will
be blinded.
1.3 Instructions:
- Instructions on when and how to fill in the online eating report.
- Instructions on how to wear the actometer at screening.
- Diet instructions at the visits in the intervention period and during weekly telephone
(or videocall) consultations during the first 4 weeks of the diet and thereafter at week
8. Diet instructions by a specialist dietitian. The diet instructions consist of a
personalized diet plan and a patient brochure with links to recipes accompanied by
verbal instructions. Diet and, if necessary medication, will be adjusted in the first
few weeks based on glucose levels in blood, complaints, practical questions and weight
developments. This will be done in the same manner as in regular patient care for adult
diabetic patients who start with the LCHF diet. Difference between this protocol and
this study is that in the protocol a diabetic nurse takes care of the medication changes
and in this study Dr. Rick Meijer is responsible, or in his absence another internist
experienced in the treatment of MIDD. Additional telephone or e-health consultations
(mijnRadboud) can be planned as frequent as necessary depending on the questions of the
patient. A specialised metabolic dietician is available 5 days a week. In the week after
the participant has to switch back to usual care there is a telephone meeting planned to
make sure the transition went safely and al information is clear for the participant.
- Instructions on how to collect a faecal stool sample
- Instructions for the blinded continuous glucose monitoring. Participant have to apply
the sensor at home in week 11 and week 23. Exclusively for MIDD patients who don't have
continuous glucose monitoring already.
- Safety instructions on how to prevent hypoglycemia and how to act in case of a
hypoglycemic incident. These instructions will be personalized based on individual
diabetes medication and blood glucose levels, the protocol is used as guideline for
these personalized instruction. This protocol is usual care in diabetes patient care and
based on the national guidelines. The instructions included medication changes. The
safety instructions on how to adapt the diet to hypoglycaemic events are included in the
diet brochure.
Investigational treatment: Low carbohydrate high fat diet Low carbohydrate (50-100
grams/day). The LCHF restricts a wide range of carbohydrate rich foods including sweets,
sugar, grains, starchy vegetables, sweet legumes, fruit juices and sweetened dairy foods and
replacing them with non-starchy vegetables, red fruits, meat, poultry, seafood, eggs, oil,
nuts, and non sweetened high fat dairy foods such as cheese, butter, cream and Greek 10% fat
yoghurt. Choosing cuts of meat higher in fat and fats, and the use of low carb alternatives
like low carb bread is encouraged. This diet is automatically high in protein. We don't want
the carbohydrate restriction to be stricter than 50 grams a day because we want a feasible
diet without de adverse events that a ketogenic diet (very strict carbohydrate restriction of
20 grams a day) has. The low carbohydrate high fat diet is part of the national diabetes
guidelines and is frequently prescribed in overweight diabetes type 2 patients with insulin
resistance.
METHODS 2.1 Measurements
The questionnaires The Gastrointestinal complaints Questionnaire contains questions on
gastrointestinal complaints (7 point Likert scale) form a validated Dutch gastro intestinal
questionnaire. We used this questionnaire in studies with mitochondrial disease before. For
severity we use a Numerical Rating Scales (NRS) stool frequency, Bristol stool chart and
laxative use is being checked.
The general study questionnaire in the intervention phase there will be questions on
feasibility and diet tolerance, adverse events and questions on diabetes medication doses
(insulin use).
- Quality of life: SF-12 questionnaire The SF-12 Health Survey (see F1.SF-12-Dutch) is a
shorter version of the SF-36 Health Survey that uses 12 questions to measure functional
health and self-administered well-being. SF12 takes approximately three minutes to
complete and it is a practical, reliable and valid measure of physical and mental
health. It is useful in large population health surveys or for applications that combine
a generic and disease-specific health survey. SF 12 is available in multiple languages,
including Dutch. It covers the following eight health domains: 1) Physical functioning
2) Limitations in usual role activities because of physical health problems 3) Bodily
pain 4) General health perceptions 5) Vitality (energy / fatigue) 6) Limitations in
social activities because of physical or emotional problems 7) Limitations in usual role
activities because of emotional problems and 8) General mental health. Two subscales are
derived from the SF-12: the Physical Component Summary (PCS) and the Mental Component
Summary (MCS). These summary scales based on the SF-12 correlate very highly with the
SF-36 version. The SF-12 uses norm-based scoring, so comparisons can be made among the
other generic health surveys. The SF-12 and SF 36 are frequently used in mitochondrial
disorders and it is advised to always combine the NMDAS with one of these quality of
life questionnaires.
- Fatigue questionnaire: short checklist individual strength The Checklist Individual
Strength is a 20-item self-reported questionnaire that captures four domains of fatigue:
1) subjective severity of fatigue 2) reduction in concentration, 3) reduction in
motivation and 4) reduction in activity. Respondents will rate the extent to which each
statement is true for them in the past two weeks on a seven-point Likert scale. The
scores are summed up accordingly. The higher the score, the higher the fatigue level. A
score between 27 and 35 suggests an increased risk for fatigue and a score above 35
suggests severe fatigue. The questionnaire has been used in various diseases, including
mitochondrial diseases.
Questionnaires will be filled in digitally as eCRF in castor by the patients directly.
Nutritional Assessment: measurements will be performed according to our standard operation
procedures Weight (kg), Weight loss (%), Height(cm) BMI (kg/m2) and body composition will be
measured with bioimpedance analysis SECA BCM 555®. With the outcome variables: Fat
percentage. Fat free Mass (FFM) (kg) and FFM Index (kg/m2), Skeletal muscle mass index
(kg/m2) and phase angle(◦).
Blood test:
- creatinine kinase (CK),
- diabetes: HbA1c and home glucose monitoring (exclusively in MIDD patients)
- lipid profile (after overnight fast/or at least 4 hours of fasting): (triglycerides,
high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol),
- kidney function (MDRD), transaminases (ALAT and ASAT), lactate
- Ketones (beta-hydroxybutyric acid and acetoactetate)
- metabolomics
Home blood test:
Diabetes control assessments will be exclusively conducted for MIDD patients. Glucose
monitoring can be done by blinded continues glucose monitors (Dexcom). Patients who are
accustomed to glucose monitoring at home as part of their routine care will not be required
to utilize the study-provided blinded monitor. Patients who use Insulin or glibenclamide,
gliclazide, glimepiride or tolbutamine will be provided with a not blinded finger prick
glucose meter to guarantee safety and to detect any low blood sugars in a timely manner.
Measuring blood glucose with this home device with a finger prick is requested when
participants experience complaints that may indicate low blood sugar, such as extreme hunger,
sweating, trembling, dizziness, palpitations, yawning, being confused or feeling restless.
Three-day food record:
A digitally three-day food record is a self-reported account of all foods and beverages
consumed by a respondent over three days, two working days and one day of the weekend. The
data will be entered by the participant in the Eetmeter app.
The aim of the use of the food record is to finetune the diet and evaluate diet adherence. It
helps patients to get more insight in their carbohydrate intake and to better manage the diet
so they are free to use it more frequently (but for the study only 3 times 3 days are
required). Intake will be automatically calculated in the eetmeter app. Data on energy
(kcal), carbohydrates (gram), protein (gram) fat (gram), fibre (grams) and water (ml) intake
will be registered.
Accelerometry:
The Activ8 is used to measure average metabolic equivalents(METS) over one week period.
Activ8 and the elaborate use instructions will be sent to patients' home (see
E4.Draaginstructie Activ8 actometer). Patients will apply the actometer and wear activ8 for
one week during 24 hours per day. The device waterproof so the participants can also wear it
during shower or swimming. Actometer activ8 has to be worn on the upper leg for 1 week at the
time in total 3 times: during the screening, week 6, and week 12. This is used to calculate
the energy expenditure for the individual diet advice[29] since the amount of activity can be
a confounder as well as an possible efficacy variable. Actometry is considered the gold
standard for activity measurements and it is a non-invasive method[30].
NMDAS:
The Newcastle Mitochondrial Disease Scale for Adults (NMDAS) is a semi-quantitative clinical
rating scale designed specifically for all forms of mitochondrial disease. It was developed
and tested in Newcastle with the aim of providing a validated and reproducible measurement of
disease progression. It is now the most widely used outcome measure in clinical trials for
mitochondrial disease. The NMDAS scale considers many parameters, including neurological
disease, diabetes, cardiac involvement. The NMDAS need to be filled during the screening and
week 12 by the metabolic specialist directly in castor.
Headache diary Frequency and severity of headages are scored with a headaches diary.
Headaches need to be registered only if occur. A NBS score for severity of the headache and
if patients took medication for the headache can be registered in the diary.
Other study parameters:
Patient characteristics: age, gender.
2.2 Randomisation, blinding and treatment allocation After signing informed consent
participants will be randomized in the intervention or control group with the castor
database. There is no blinding or treatment allocation in this study. Upon arrival on the
screening, the participants receive an ID code. The first participant will be number one and
so on.
2.3 Withdrawal of individual subjects Subjects can leave the study at any time for any reason
if they wish to do so, without affecting future management and treatment. The investigator
can decide to withdraw a subject from the study for urgent medical reasons.
2.4 Replacement of individual subjects after withdrawal Patients will not be replaced after
withdrawal. However, if patients do not meet the inclusion and exclusion criteria based on
the results from the first visit, then these patients will be replaced.
2.5 Follow-up of subjects withdrawn from treatment Patients will be asked if they are willing
to complete the final study visit after they stopped the diet. They are asked why they
stopped the diet but they are not obligated to answer this or come to the closing visit.
3. STATISTICAL ANALYSIS
Descriptive analyses Statistical analysis will be performed using SPSS statistics version 24
(IBM). Baseline characteristics will be reported, at timepoint 0 weeks, as means ± SD for
normally distributed variables, as median and IQR for non-normally distributed variables and
as a percentage of the total population for the categorical variables.
