Type 1 diabetes (T1D) is by far the most common chronic, serious, life-threatening
disease in Sweden, and tends to become an extremely serious global problem. Residual
insulin secretion is of crucial importance to facilitate treatment, prevent acute and
late complications and improve quality of life.
Primary objective: To evaluate the effect on preservation of residual beta cell function
but treatment with Verapamil Secondary objectives: To evaluate safety, but also clinical
efficacy of Verapamil treatment such as blood glucose control and prevention of acute
complications, and immunological effect on the disease process
Primary outcome:
• Change in C-peptide AUCmean 0-120 min) during an MMTT from baseline to month 24.
Secondary outcome:
Change in C-peptide fasting and 90 minute value during an MMTT from baseline to
month 24
Proportion of patients with peak C-peptide > 0.20 nmol/l at month 24
Hemoglobin A1c (HbA1c), change between baseline and subsequent visits
Exogenous insulin dose per kg body weight and 24 hours, change between baseline and
subsequent visits
Safety and tolerability
Trial population:
Patients must be 4.0 - 9.99 years old, and diagnosed with type 1 diabetes (T1D) within
the previous 3 months at the time of screening.
Number of subjects: Part A: 6 Part B: 30 (In total 36)
Inclusion criteria:
Informed consent given by patients and caregivers/parents Type 1 diabetes according
to the ADA classification within the previous 3 months at the time of screening
Age 4.00 -9.99 years at Diagnosis of Type 1 diabetes
Fasting C-peptide >0.12 nmol/ml
Elevated levels of any diabetes-related antibody/ies (eg GADA, IAA, IA-2A, ZnT8A )
is/are present.
Exclusion criteria:
Cardiac disease/ problems
Abnormal ECG
history of abnormal blood pressure
Previous or current treatment with immunosuppressant therapy (although topical or
inhaled steroids are accepted)
Continuous treatment with any inflammatory drug (sporadic treatment e.g. because of
headache or in connection with fever a few days will be accepted)
Treatment with any oral or injected anti-diabetic medications other than insulin
A history of anaemia or significantly abnormal haematology results at screening
Participation in other clinical trials with a new chemical entity within the
previous 3 months
Inability or unwillingness to comply with the provisions of this protocol
A significant illness other than diabetes within 2 weeks prior to first dosing.
However treated celiac disease and hypothyroidism with adequate treatment will be
accepted.
Deemed by the investigator not being able to follow instructions and/or follow the
study protocol
Intervention:
The study is a Phase I/II trial, with two parts: A. 6 patients participate in an open
controlled study without any placebo with the primary aim to evaluate safety. After a
baseline evaluation including ECG, physical examination, mixed Meal Tolerance Test
evaluating residual beta cell fuction, these patients will be treated for 12 months with
Verapamil 3-6 mg/kg body weight/24 hrs, divided into two daily doses. When these 6
patients have been followed for 6 months, and safety and tolerability is regarded as
good, part B will start: In part B the next 30 patients will be randomized 1:1 in a
double-blind placebo-controlled study into two arms: 15 patients will receive active
treatment for 12 months with Verapamil 3-6 mg/kg body weight/24 hrs divided into two
daily oral doses, while 15 patients will receive placebo in two daily doses for 12
months. Efficacy will be evaluated with MMTT and clinical response ( insulin dose/kg body
weight/24 hrs, HbA1c, and CGM data on Glucose Time in Range), from baseline and after 12
and 24 months.
Investigational medicinal product(s), dosage, administration: 3-6 mg/kg body weight/24
hrs of Verapamil ( Isoptin) is given per os two times per day Ethical considerations,
benefit/risk: There is a great benefit of preservation of residual insulin secretion, and
therefore therapies aiming at preservation of this function justifies treatments that are
quite heavy, even dangerous and expensive. Thus it has been regarded as justified to
treat even children with Type 1 diabetes at onset with drugs like monoclonal antibodies
against the CD3-receptor, which causes adverse events in principally all patients, some
even quite serious adverse events and risks. Even cytostatics have been used.
The investigators will here use oral Verapamil, a drug which is used as antihypertensive
treatment in different ages, even in children in the neonatal period, with limited
adverse events and risks. Verapamil treatment has shown encouraging results preserving
beta cell function in Type 1 diabetes in adults, and the investigators expect to get
similar positive effects also in young children, in whom so far no immune intervention
has shown efficacy.
Thus, there is a clear possibility of therapeutic benefit, whereas the risk is very
small, which makes the trial ethically justified.
