Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03791242 |
| Other study ID # |
0199138/2018 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 21, 2019 |
| Est. completion date |
May 19, 2021 |
Study information
| Verified date |
June 2021 |
| Source |
University of Roma La Sapienza |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Obstructive Sleep Apnea Syndrome (OSAS) and obesity tend to coexist and are often associated
with arterial hypertension, dyslipidaemia, and insulin resistance [1]. Polysomnography (PSG)
is the standard technique for diagnosing OSAS and determining its severity [2]. The results
of the examination provide the Apnea-Hypopnea Index [AHI], or the Respiratory Disturbance
Index [RDI]), which will be used to quantify apnea and classify its severity based on an
international score. In general, an AHI scoring less than 5 is considered "normal" (5-15 mild
sleep apnea; >15 moderate sleep apnea; ≥30 severe sleep apnea).
In order to improve those parameters in obese patients who have been diagnosed with OSAS and
are candidates for BS (BS), national and international guidelines recommend preoperative CPAP
(Continuous Positive Airway Pressure) treatment in order to reduce anaesthesia risks [3-6].
Furthermore, several studies report that obese OSAS patients benefit from preoperative weight
loss [1,7] (in terms of AHI index, night snoring and arterial hypertension).
Obese patients who are candidates for BS often go on a preoperative diet in order to decrease
weight and liver volume (especially of the left lobe) and correct any vitamin/mineral
deficiency. The results of a recently published study show that 4 weeks of Ketogenic
Micronutrient Enriched Diet (KMED) significantly reduce body weight, liver lobe volume and
vitamin/mineral deficiencies in obese patients who prepare to undergo BS [8], with resulting
foreseeable reduction of intraoperative complications and surgical time.
To date, there are no prospective multicenter randomized trials demonstrating whether a
preoperative ketogenic diet associated with CPAP use improves OSAS versus treatment with CPAP
alone, with the possibility of reducing the preoperative treatment period.
Aim of the study: To assess the clinical advantage in combining two preoperative strategies
(CPAP + KMED) compared to preoperative treatment with CPAP alone, for the reduction of
surgical risks in morbidly obese patients with severe OSAS who are scheduled for BS.
Description:
A recent clinical study published in 2014 on the New England Journal of Medicine found that
often even an initial modest body weight reduction can favourably modify apnea events and
severity during the night, with the latter that can be reduced by about 30% (AHI) for a 10%
weight reduction compared to the initial weight [1]. However, considering the average AHI
data reported by the authors, which do not include post-treatment information, statistical
elements at our disposal are insufficient to assess the "effect size". Therefore, a sample of
65 patients per group will be needed for the evaluation of the primary endpoint (statistical
significance of 5% [two-tailed], 80% power, "effect size" 0.25, calculated using the G* Power
software, Düsseldorf, Germany). A total of 66 patients will be enrolled (22 patients per
participating site) on the baseline assumption of a dropout of 10%. Most drop-outs may result
from CPAP use and, in particular, discomfort experienced by the patient with tube and facial
mask, difficult acceptance because of psychological reasons (shame or negative expectations
in terms of partner judgment), or subjective feeling of claustrophobic suffocation or
anxiety. The expected drop-out for KMED with the Ketocompleat protocol is 15%. Indeed, in
Schiavo et al [8] study, most patients (86%) showed high acceptability of the Ketocompleat
ketogenic protocol prescribed in the four weeks of preoperative treatment, and the only side
effect reported was mild headache with associated modest halitosis, especially during the
initial treatment days, which, however, did not prevent patients from continuing with the
protocol.
Experiment design and patient randomization
Spontaneous, prospective, comparative and multicentre trial including 66 patients with severe
OSAS (polysomnogram with AHI≥30) suitable for gastric bypass surgery, and randomized into 2
groups:
GROUP 1: 33 morbidly obese patients with severe OSAS and suitable for gastric bypass surgery,
who underwent 4 weeks of CPAC treatment (these patients will not be required to change their
eating habits) according to the standard; GROUP 2: 33 morbidly obese patients with severe
OSAS and BS candidates who underwent CPAC + KMED treatment for 4 weeks.
Randomization will be conducted via permuted-block design (PBD), with stratification of
patients based on age, gender, and enrollement site Preoperative ketogenic
micronutrient-enriched diet: The ketogenic diet has been used for many years in clinical
settings [9]. Given its safety and effectiveness in determining weight loss, associated with
optimal adherence and patient compliance, the ketogenic diet has recently been used by
several obesity surgery centers in the preoperative management of obese patients who are
candidates for BS [8, 10-11]. The validated Ketocompleat protocol [8] will serve as the KMED
of choice. In particular, the protocol will provide a diet with ketogenic characteristics
that patients will have to follow for breakfast, snack, lunch and snack, and replacement of
the evening meal with the Ketocompleat ketogenic supplement. Figure 1 shows a daily diet
sample.
In short, to ensure that all patients follow the same diet, the investigator will use the
software (https://www.eatthismuch.com) to develop two ketogenic diet plans (plan 1, days
1-14; plan 2, days 15-28), containing specific amounts of foods to be consumed. Each
ketogenic plan will comprise: 1150 to 1250 kcal/day, of which 4% carbohydrates, 71% fat, and
25% proteins. The composition of the supplement to use for the trial (Ketocompleat, MVMedical
Solutions, Serravalle, Republic of San Marino) is shown in Table 1. Ketocompleat is a
supplement included in the Ministry of Health's food supplement register (code 94721); given
its carbohydrate-free formulation, it can easily be associated to a low-carbohydrate
ketogenic diet. The diet plans and the Ketocompleat supplement will be provided free of
charge to all trial participants by MVMedical Solutions, which will have no role in designing
trial and patient enrollement in the different participating sites, or in processing any
trial-related data.
Patient adherence to the prescribed preoperative diet will be confirmed through the following
scientifically validated tests: 3-Day Estimated Food and Records and 72-h Recalls [8], while
the presence of ketone bodies in the urine (Ketur-Test, Roche Diagnostic, Milan, Italy)
associated with weight loss will be used as the patient compliance index. The Ketur test will
be performed in outpatient mode during the weekly diet check.
Polysomnography
Polysomnography is a sleep study that collects a variety of parameters and conditions, such
as oxygen saturation, heart rate, presence (or absence in the case of apnea) of airflow
through mouth and nose, presence (or absence) of thoracic and abdominal movements, position
held by the subject during sleep, and snoring during sleep. By analysing these data, it will
be possible to define: number of episodes of haemoglobin desaturation during sleep
(desaturation index per hour - ODIindex), presence or absence of apnea during sleep,
differentiating between true apnea true (absence of air flow) and hypopneas (air flow
present, though substantially reduced), determination of "obstructive" "central" or "mixed"
apnea/hypopnea, hourly frequency of apnea/ hypopnea ( apnea/hypopnea events per hour or AHI
index), which allows defining the degree of severity of the disorder (disease stage), AHI in
supine and non-supine position (often this datum documents greater apnea frequency in the
supine position compared to data relating to the patient in lateral decubitus), and snoring
time during sleep. In order to evaluate the clinical advantage offered by the combination of
the two preoperative strategies (CPAP and ketogenic diet therapy) compared to CPAP
preoperative treatment alone, for the reduction of the surgical risk in morbidly obese OSAS
BS candidates, patients of both groups will undergo polysomnography before the trial and
after 4 weeks of CPAP alone or combined CPAP + KMED treatment. The tolerance interval for PSG
execution at the end of the treatment is 7 days; otherwise, patients will be considered
drop-outs.
CPAP-type ventilator prescription CPAP use is the gold standard for the treatment of sleep
apnea syndrome. The CPAP device consists of a small fan connected to the patient through a
tube and a facial mask (nasal or oronasal). This device provides continuous air flow that
maintains the airways open, preventing the collapse (closing) of the critical points
responsible for respiratory obstruction during sleep, thus avoiding or limiting sleep apnea.
Patients with severe OSAS who are BS candidates will be treated with CPAP only at night
(Group 1), or CPAP at night + KMED daily (Group 2), for 4 weeks.
Preoperative investigations and after 4 weeks of CPAP or CPAP + KMED treatment
In the BS Centers participating in the trial, both experimental groups will undergo the
following evaluation:
- Complete blood count with WBC differential, triglycerides, total cholesterol, HDL
cholesterol, LDL cholesterol, triglycerides, GOT, GPT, ΥGT, nitrogen, creatinine, urea,
iron, ferritin, ketone bodies, baseline glucose, baseline insulin, and CRP
- Body weight, height and BMI calculation
- Waist and hip circumference
- Chest X-ray
- Blood gas analysis
- Spirometry
- Polysomnography
Laboratory/instrumental clinical analyses, polysomnography and CPAP will be performed in the
sites participating in the project; data obtained will be evaluated by a Pneumologist, while
the statistical analysis will be entrusted to a Biostatistician.
Inclusion criteria: patients of both sexes with BMI ≥35 with severe OSAS; age between 18-65
years; non-smokers or who have quit smoking for at least 3 months.
Exclusion criteria: kidney and/or liver conditions that would make a KMED diet unsuitable
(creatinine levels >1.8 mg/dL or liver enzyme levels (glutamic pyruvic transaminase [GPT] or
glutamic oxaloacetic transaminase [GOT]) less than three times over the upper normal
threshold, and psychological problems that would make CPAP treatment problematic. Patients
with obesity >60 BMI.
Primary endpoint: evaluate the effect of combined (CPAP + KMED) therapy vs CPAP on the AHI
after 4 weeks. Secondary end points: evaluate CRP levels, arterial pressure and lipid panel
(total cholesterol, HDL, LDL and triglycerides) in the two study groups.
