To examine the effects and safety of methylprednisolone combined with diazoxide on the progression of type 1 diabetes at the onset of disease
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Autoimmune disorders
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The difference of the 2 hour MMTT mean C-peptide AUC between the treatment and
placebo group after 24 months. The MMTT is also performed at baseline, 17 days,
6 weeks, 14 weeks, 12 months and at 24 months.
Secondary outcome
• The proinsulin and glucose concentration before and during the MMTT at
baseline, 2 weeks, 6 weeks, 14 weeks, 26 weeks, 12 months and 24 months.
• Insulin use (assessed as the average IU/kg/day during the last week) and
HbA1c at baseline, 6 weeks, 14 weeks, 26 weeks, 28 months, 12 months and 24
months.
• Time spent with interstitial glucose in hypoglycemic range (<3.9), target
range (4.0-10) and hyperglycemic range (>10.0), standard deviation, coefficient
of variance and mean amplitude of glucose excursions (MAGE), as determined by
open continuous glucose measurement (CGM) during the treatment period and a
blinded CGM at 12 and 24 months
• General and diabetes specific quality of life, diabetes self-management,
hypoglycaemic distress and hyperglycaemic distress assessed by questionnaire at
baseline, after 14 weeks, 8, 12 months and 24 months.
• Occurrence of adverse events and severe adverse events (specifically
infections)
• Pancreas inflammation as determined by FDG-PET scan, before and 3 months
after methylprednisolone or placebo
• Effect on β-cell auto-immunity and β-cell stress measured by
o Number of immune cells determined by FACS analysis
o T cell responsiveness to diabetes specific antigens (including
Insulin-defective ribosomal products (DRiPs)) as determined by LST, compared to
other antigens
o Number of CD8+ autoreactive T cells as determined by tetramer using the Q-DOT
assay
o Level or quality of beta-cell autoantibodies (eligible autoantibodies: anti
GADA or IA-2A) by commercial ELISA.
Background summary
: Type 1 diabetes is an auto-immune disease that leads to destruction of beta
cells and thereby inadequate endogenous insulin secretory capacity. Currently,
treatment consists of intensive insulin therapy. Despite medical and
technological advances, many challenges remain. Treatment with intensive
insulin therapy is a trade-off between long-term complications and
hypoglycaemia. Therefore, type 1 diabetes is associated with increased
mortality, even when glycaemic regulation is optimal1. In contrast, endogenous
insulin production has been shown to improve both glycaemic regulation, beyond
the limits of insulin treatment, and reduce the risk of hypoglycaemia2. Many
patients with type 1 diabetes have a large β-cell reserve at diagnosis,
sometimes characterised by a *honeymoon phase*. During this period no or little
exogenous insulin therapy is required3. This β-cell reserve quickly depletes
during the course of the disease. If these residual β-cells can be retained,
patients will have improved glycaemic control and fewer hypoglycaemic events.
The combination of intensive anti-inflammatory (high dose steroid) treatment
and β-cell protective (diazoxide) treatment might effectively stop or
significantly reduce the auto-inflammatory process while preventing the
steroid-associated β-cell detrimental side effects in patients with new onset
type 1 diabetes mellitus. Therefore, we expect that the combination of these
two therapies will potentiate each other.
Study objective
To examine the effects and safety of methylprednisolone combined with diazoxide
on the progression of type 1 diabetes at the onset of disease
Study design
This is a double-blind randomized placebo-controlled trial.
Intervention
The 21 participants in the treatment group will receive a three-day intravenous
methylprednisolone 1000mg course followed by 12 weeks prednisolone in a taper
dose, combined with diazoxide 2dd 200mg from three days before the
methylprednisolone. At the first of methylprednisolon the dose will be raised
when there are no signs of (orthostatic) hypotension to 2dd400mg until week 2
and diazoxide 2dd 200mg from the third week until one week after cessation of
the prednisolone. The placebo group will receive placebo in an identical
schedule.
Study burden and risks
Since corticosteroids cause insulin resistance and diazoxide inhibits insulin
secretion, more exogenous insulin will be needed to control glucose variation
in the treatment group during the first three months. After the treatment, less
exogenous insulin requirement is expected. High dose corticosteroids and
diazoxide have side effects, but these are manageable and safety parameters
will be monitored intensively during the treatment period.
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
• Age 16 - 40 years
• Diagnosis of type 1 diabetes in the last eight weeks
• Presence of β-cell autoantibodies (eligible autoantibodies: anti-GAD and
anti-IA-2)
• Of Caucasian ethnicity
• Mixed meal test stimulated C-peptide AUC0-120min >0.2 nmol/L
Exclusion criteria
• Unmanageable metabolic instability (ketoacidosis)
• Current use of other immunosuppressive or immunomodulatory therapy
• Current acute infection
• Current parasitic infections
• Heart failure
• Hyperuricemia
• History of malignancy
• (Possible) previous tuberculosis infection
• Active ulcus ventriculi or duodeni
• Use of CYP3A4 inhibitors of inducers
• Known hypersensitivity or intolerability to one of the investigational
products
• Female patients who are pregnant or breastfeeding
• Female patients who are fertile and unwilling to use adequate contraception
during the 12 month study period
• Recent patient*s involvement in other studies which in the opinion of the
investigators could affect the safety of the patient or the result of the study
• Any condition which, in the opinion of the Investigator might jeopardise the
subject*s safety or compliance with the protocol
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-000686-37-NL |
| CCMO | NL65374.058.18 |
| Other | Volgt |