The principal aim of this proof-of-concept exploratory study is to determine whether a full randomised controlled trial to test glibenclamide in a large cohort of CS patients is justifiable and feasible and to optimize its design. We specifically…
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Condition
- Cardiac and vascular disorders congenital
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Intervention
Outcome measures
Primary outcome
Primary study parameter
The primary outcome parameter of the exploratory study will be the mean change
in the number of hair follicle per cm2 in predefined body areas affected with
hypertrichosis (cheek, forehead, arm).
Dermascopy pictures will be taken and evaluated using a computerized system
(either Folliscope or Trichoscan). The system is able to pinpoint the area of
interest, count the hairs and/or hair follicle present in this area as well as
measure thickness, density and growth. Additionally, results can be compared
over time.
Secondary outcome
Secondary study parameters:
Secondary outcome parameters will include parameters of safety (hypoglycemia,
renal function) and efficacy of glibenclamide in treating cardiovascular,
lymphatic, facial and dermatological effects of this condition. Based on our
data from natural history studies collected over the past 5 years, we have
identified a number of clinical characteristics whose possible reduction we
intend to investigate during chronic exposure to glibenclamide.
1. Hypoglycemic events (safety parameter)
The prevalence of dose-related minor and major hypoglycemic events will be
assessed. Patients will be provided with a continuous glucose sensor and
instructed by a specialized nurse how to handle in case of low blood glucose
and recognize hypoglycemic symptoms. They will upload their 24h glucose
profiles daily during the 2x2 weeks run-in period and weekly thereafter.
Hypoglycemia will be categorized as follows (EMA 2012): documented symptomatic
hypoglycemia (blood glucose <3.9 mmol/L), asymptomatic hypoglycemia (blood
glucose <3.9 mmol/L), severe hypoglycemia (requiring assistance from another
person), relative hypoglycemia (blood glucose > 3.9 mmol/L).
2. Serum creatinine (safety parameter)
Serum creatinine is produced at a constant rate provided renal function is
conserved and will be used as proxy for glomerular filtration rate and
therefore an indicator of overall kidney function. Blood samples for creatinine
measurements from serum will be taken.
3. Change from baseline in cardiovascular abnormalities
Cardiovascular abnormalities will be evaluated by MRI, echocardiography,
24-hour heart rhythm monitoring and standard cardiac exercise test.
4. Changes from baseline in swelling/edema in the leg
Edema will be measured applying method of Kuhnke (Kuhnke & Asdonk, 1986) where
measurement of leg circumference by tape will be taken at the malleolar level
and every 4 cm for eight leg segments.
5. Change from baseline in facial abnormalities
3D images of the face will be taken and analyzed using dense surface modelling
and closest mean classification as described in Roessler et al. (2020).
6. Changes from baseline in dermatological abnormalities
We will take clinical photographs of body parts with hypertrichosis, collect
hair samples and take a scalp/forehead biopsy as described in Ohko et al.
(2020). Patient satisfaction with hair growth and frequency of shaving
necessary will be measured by asking patients to fill in a questionnaire
including a Likert scale.
7. Change from baseline in skin-related phenotypes
During a physical exam, we will take clinical photographs of body parts
revealing key skin abnormalities seen in CS. Clinical pictures will be blindly
evaluated by specialists to give qualitative scores.
8. QOL questionnaire
The questionnaire will measure physical, social, and emotional aspects of
functioning, and common symptoms of CS and GLB treatment.
9. Changes from baseline in vital signs
Heart rate, systolic (sitting down) and diastolic (standing up) blood pressure
will be measured.
10. Anthropometric measurements.
We will measure height, weight and head size during every visit.
Background summary
Cantú syndrome (CS) is a rare autosomal dominant genetic condition that affects
multiple organ systems. It is caused by gain-of-function mutations in ABCC9 and
less commonly KNCJ8 which encode subunits of an ATP-sensitive potassium
channel. Currently, there is no therapy for CS patients available yet. However,
it is postulated that sulfonylureas, like glibenclamide, would close the
overactive potassium channel present in patients. These compounds are already
successfully used in clinic to treat patients with diabetes resulting from
missense mutations in ABCC8.
Study objective
The principal aim of this proof-of-concept exploratory study is to determine
whether a full randomised controlled trial to test glibenclamide in a large
cohort of CS patients is justifiable and feasible and to optimize its design.
We specifically intend to assess the efficacy and safety of glibenclamide in
individuals with CS.
Primary objective:
To determine whether giving glibencamide to CS patients can efficiently reverse
hypertrichosis. Thus, we will perform dermascopy pre-, and post-baseline in
order to assess changes in the amount of hair follicle in predefined body areas
as well as measure thickness, density and growth of hair.
Secondary objectives:
Secondary objectives involve safety, further evidence of efficacy and
collecting of experience and data a pivotal study can be based on.
1. Although safety has already been checked in healthy individuals, we will
determine safety of glibenclamide in CS patients. The main concern of treating
CS patients with glibenclamide is that individuals who do not have diabetes are
potentially at risk to develop hypoglycemia as a side effect.
2. To determine efficacy of glibenclamide in reversing (i) cardiovascular
abnormalities focusing on cardiomegaly, aortic dilation, tortuosity, high-state
output and exercise intolerance, (ii) swelling/edema in the leg, (iii)
distinctive facial features as described in Roessler et al. and (iv) further
skin- and hair-related abnormalities associated with CS.
2. To collect data to inform sample size calculations for the primary outcome
measures for use in a future full-scale phase II/III trial.
3. To estimate treatment period, appropriate outcome measurements and effect
size for future trial.
Study design
We intend to perform a proof-of-concept early phase exploratory clinical study
which will be an open- label, single-arm, non-randomized, uncontrolled
intervention study for only a limited number of Dutch patients due to the
overall rarity of CS. Thus, all participating patients will receive
glibenclamide and we will not include a control group. Baseline measurements
will be performed before commencement of glibenclamide treatment and patients
will be their own controls. The study will last for 9 months. After undergoing
baseline measurements, CS patients will start on a low dose of glibenclamide
(2.5 mg) and patients will monitor their blood glucose with a common glucometer
for hypoglycemia, which is the most likely adverse effect expected in
non-diabetic patients. Patients will be seen monthly for the first 6 months and
one more time after another 3 months.
Intervention
The study drug glibenclamide, also called Glyburide, is a second-generation
sulfonylurea drug working as an oral antihyperglycemic agent used for the
treatment of non-insulin-dependent diabetes mellitus. It belongs to the
sulfonylurea class of insulin secretagogues, which promote increased insulin
secretion and reductions in blood glucose due to its inhibitory action on
pancreatic-expressed SUR1-dependant KATP channel isoforms (ABCC8).
Glibenclamide was approved by the EMA for use in Type II diabetes nearly 30
years ago, is readily available at pharmacies and is inexpensive. The drug is
available in scored 5 mg tablets and therefore easily divided in two 2.5 mg
doses. It has been successfully used for long-term treatment of Type II
diabetes in children and adults. It is generally well tolerated and
hypoglycemia is its main side effect.
The usual starting dose of glibencamide in adults with type 2 diabetes is 2.5
mg once a day. During the exploratory study we propose to start at a lower dose
in CS patients as they do not have diabetes and therefore are at risk to
develop hypoglycemia. We will start with a run-in period of 2 weeks with 1.25
mg once a day and monitor closely for signs and symptoms of hypoglycemia and we
will monitor blood glucose using a continuous glucose sensor. Patients will be
instructed by a specialized nurse how to recognize hypoglycemic symptoms and
how to handle them in case of a hypoglycemia. In case patients develop
hypoglycemia on this dose, they will be excluded from the study. In case they
tolerate 1.25 mg per day well, we will increase the dose after 2 weeks to 2.5
mg a day for another 2 weeks.
Study burden and risks
Most tests, except for the skin biopsy and the continuous glucose sensor, will
be non-invasive. Patients will be carefully instructed how to recognize
hypoglycemia and how to handle when blood glucose drops < 3.9 mmol/L. 24h
glucose profiles will be uploaded and evaluated daily in the run-in period and
weekly thereafter. Hence, we believe that although hypoglycemia is a serious
adverse event, the 24h glucose monitoring and the instructions will mitigate
this risk substantially. Other side effects reported with Glibenclamide are
seen in less than 2% of treated patients. Given the promising pre-clinical
data, CS patients might directly benefit from treatment if glibenclamide
ameliorates CS related features.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
1. As the majority of CS patients reveal a mutation in ABCC9 and we aim to
create a homogenized study population, only, otherwise healthy, patients with a
confirmed diagnosis of CS via molecular genetic testing, with a mutation in
ABCC9 will be eligible.
2. 16 years of age or older.
3. No history of sulfonamides or thiazides allergies.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
1. All patients without a molecularly proven diagnosis of Cantú syndrome are
excluded from this study.
2. Patients with a history of a sulfonamides or thiazides allergy
3. CS patients who are deemed poor candidates by the PI for the study based on
additional medical concerns, not related to CS, including epilepsy, diabetes
mellitus, intellectual deficit. As far as we are aware there are no cases in
our cohort who are now suffering from additional medical concerns.
4. Pregnant women.
5. Patients with known G6PD deficiency.
6. Patients with known chronic kidney or liver disease.
7. Patients who take non-selective beta-blockers due to a possible
interaction with the study drug glibenclamide.
Design
Recruitment
Medical products/devices used
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004651-36-NL |
| CCMO | NL71289.018.20 |