Primary objective:The primary objective is to evaluate the efficacy of Diamyd, administered into lymph nodes in combination with an oral vitamin D regimen, compared to placebo in terms of preserving endogenous insulin secretion as measured by C-…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in C-peptide (Area Under the Curve [AUC]mean 0-120 min) during a Mixed
Meal Tolerance Test (MMTT) between baseline to 15 months.
Secondary outcome
Key secondary endpoints:
• Change in insulin-dose-adjusted HbA1c (IDAA1c) between baseline and 15 months
• Change in Hemoglobin A1c (HbA1c) between baseline and 15 months
• Change in daily exogenous insulin consumption between baseline and 15 months.
Secondary endpoints;
• Other variables that indicate Diabetes Status such as plasma C-peptide,
variability of blood sugar, and number of self-reported hypoglycemia.
• Variables that indicate treatment safety such as occurrence of adverse events
(AEs), physical examinations, hematology, urine analysis, injection site
reactions, GAD65A titer, vital signs and clinical chemistry.
• Variables that indicate effects on the immune system such as serum
autoantibodies (and isotypes) to GAD65, serum cytokine levels, secretion of
cytokines by immune cells in response to GAD65 stimulation, and proportions of
immune cells in blood.
• Measurements of patient QoL by questionnaire.
Background summary
Type 1 diabetes is an autoimmune disease in which beta cells in the pancreas -
the cells in the body that create insulin - are broken down by the patient*s
own immune system (white blood cells). Although today patients with type 1
diabetes are intensively treated with insulin, it can still be difficult to
maintain a good sugar balance. This can lead to serious acute complications
such as unconsciousness due to low blood sugar (insulin shock) or acidosis
(diabetic coma). In the long term, an unsatisfactory blood sugar balance can
lead to serious damage to the kidneys, eyes, nerves and heart. Therefore, it
would be valuable if a treatment could be found that was able to stop the
degradation of the beta cells by the patient*s own immune system. Preserving
insulin production may make treatment easier and improve blood sugar balance,
which in turn may reduce the risk of acute and later complications.
The destruction of the pancreatic beta cells in T1D is associated with cellular
immune responses to the pancreatic islet cells, genetic susceptibility
involving genes thought to modulate the immune response, and the presence of
autoantibodies against several islet beta cell components (i.e., autoantigens)
, In addition, as these T1D-associated autoantibodies often precede the
clinical onset of disease, GAD65A, i.e. autoantibodies directed against
glutamic acid decarboxylase (GAD) with a molecular weight of 65 kDa (GAD65A),
insulinoma-associated protein 2 (IA-2A), insulin (IAA) or zinc T8 (ZnT8A) are
widely recognized not only as diagnostic markers for autoimmune beta cell
destruction, but as predictive markers for the disease.
Diamyd is an investigational drug composed of the recombinant human GAD65
(rhGAD65) protein formulated in a sterile, non-pyrogenic phosphate buffered
saline containing the aluminum hydroxide (alum) adjuvant, Alhydrogel. Diamyd
therapy aims at intervening in this destructive process by modulating the
immune system in a discrete, antigen-specific fashion to prevent the
destruction of beta cells. Thus, the goal of Diamyd therapy would be to slow
down or halt the ongoing autoimmune destruction of pancreatic islet beta cells
in order to preserve the largest possible amount of endogenous insulin
production. In the proposed treatment regimen, exogenous oral Vitamin D
treatment may improve the efficacy both via effects on the immune system and
mechanism directly on the beta cells to increase beta cell function and limit
the autoimmune reaction. This may improve blood sugar control and at the same
create a fertile field for Diamyd to induce long term tolerability.
The hypothesis is that the proposed treatment regime will rebalance islet cell
interactions and the pancreatic immune environment to increase beta cell
function and limit the autoimmune reaction. This will improve blood sugar
control and at the same create a more fertile field for the GAD65 antigen
specific immunotherapy Diamyd to induce long term tolerability.
Study objective
Primary objective:
The primary objective is to evaluate the efficacy of Diamyd, administered into
lymph nodes in combination with an oral vitamin D regimen, compared to placebo
in terms of preserving endogenous insulin secretion as measured by C-peptide.
Secondary objectives:
The secondary objectives are to compare Diamyd, administered into lymph nodes
in combination with an oral vitamin D regimen and placebo treatment with
respect to the effects on the diabetes status, treatment safety, immune system
and quality of life (QoL) of the patients.
Study design
The study is a 2-arm, randomized, double-blind, placebo-controlled,
multicenter, clinical trial. Eligible patients will receive injections of
Diamyd/placebo into an inguinal lymph gland at three occasions, with one month
intervals in combination with an oral vitamin D/placebo regimen (starting 1
month ahead of injections) during 4 months. All patients will continue to
receive intensive insulin treatment from their personal physicians during the
whole study period. The patients will be followed in a blinded manner for a
total of 15 months. All patients that are ongoing, i.e. have not performed
Visit 7 (15 months visit) when protocol version 7 is approved and implemented,
will be asked to participate in the Extension Study
Period which include Visit 8 at month 24.
Intervention
The patients will be assessed for eligibility at the screening visit (Visit 1)
2 to 4 weeks prior to start of oral treatment with vitamin D. On Visit 2 (Day
1), patients eligible for the study will be randomized to 1 of 2 treatment
groups:
• Approximately 53 patients will be assigned to receive i) three (3)
intralymphatic injections with 4µg Diamyd on Days 30, 60, and 90 and; ii) oral
vitamin D 2000 IE daily for 4 months (from Day 1 through Day 120)
• Approximately 53 patients will be assigned to receive i) three (3)
intralymphatic injections of Placebo for Diamyd on Days 30, 60, and 90 and; ii)
oral Placebo for vitamin D once a day for 4 months (from Day 1 through Day 120)
Study burden and risks
Giving a blood sample can cause discomfort such as bruising and tenderness. It
can also be perceived as difficult to be fasting before the visits during which
blood samples will be taken.
Treatment with the Diamyd® vaccine does not cause any known side effects or
risks of particular severity or seriousness anticipated based on the
toxicological data in animals or prior studies in humans, except that patients
have reported injection site reactions, such as e.g. itching, edema,
tenderness, bruises, and pain. Previous studies have shown that Diamyd® is safe
and patients who have received the vaccine have tolerated it well. Patients
treated for allergies by injection into a lymph node have experienced the stick
of the needle in the lymph node as less unpleasant than having a blood sample
taken from the arm, and patients injected with Diamyd® in a lymph node in the
groin have not stated that they experienced significant discomfort.
There are no anticipated risks of vitamin D supplementation at the dose to be
administered in this study, although toxic levels may induce hypercalcemia with
symptoms such as tiredness, euphoria, nausea, drowsiness, weight loss, thirst,
polyuria, nefrocalcinosis and renal failure. Additional symptoms of vitamin D
toxicity include electrocardigraph changes, arrhythmia and pancreatitis.
As Diamyd has proven to be well tolerated in a large number of patients in
previous studies, the possibility of therapeutic benefit outweighs the risks.
Kungsgatan 29 Kungsgatan 29
Stockholm SE-111 56
SE
Kungsgatan 29 Kungsgatan 29
Stockholm SE-111 56
SE
Listed location countries
Age
Inclusion criteria
1. Informed consent given by patients and/or patient*s parent(s) or legal
acceptable representative(s) (guardian(s)) according to national regulations
2. T1D according to the ADA classification diagnosed <=6 months at the time of
screening
3. Age: >=12 and <25 years old
4. Fasting C-peptide >=0.12 nmol/L
5. Positive for GAD65A but < 50 000 IU/ml
6. Females must agree to avoid pregnancy and have a negative urine pregnancy
test.
Patients of childbearing potential must agree to use adequate contraception,
until one (1) year after the last administration of Diamyd. Adequate
contraception is as follows:
For females of childbearing potential:
a. oral (except low*dose gestagen (lynestrenol and norestisteron)), injectable,
or implanted hormonal contraceptives
b. combined (estrogen and progestogen containing)
c. oral, intravaginal or transdermal progesterone hormonal contraception
associated with inhibition of ovulation
d. intrauterine device
e. intrauterine hormone-releasing system (for example, progestin*releasing coil)
f. bilateral tubal occlusion
g. vasectomized male (with appropriate post vasectomy documentation of the
absence of sperm in the ejaculate)
h. male partner using condom
i. abstinence from heterosexual intercourse , For males of childbearing
potential:
a. condom (male)
b. abstinence from heterosexual intercourse
Exclusion criteria
1. Previous or current treatment with immunosuppressant therapy (although
topical or inhaled steroids are accepted)
2. Continuous treatment with anti-inflammatory drug (sporadic treatment e.g.
because of headache or in connection with fever a few days will be accepted)
3. Treatment with any oral or injected anti-diabetic medications other than
insulin
4. Treatment with Vitamin D, marketed or not, or unwilling to abstain from such
medication during the trial
5. A history of anemia or significantly abnormal hematology results at screening
6. A history of epilepsy, head trauma or cerebrovascular accident, or clinical
features of continuous motor unit activity in proximal muscles
7. Clinically significant history of acute reaction to vaccines or other drugs
in the past
8. Treatment with any vaccine, including influenza vaccine, within 4 months
prior to planned first study drug dose or planned treatment with any vaccine up
to 4 months after the last injection with study drug.
9. Participation in other clinical trials with a new chemical entity within the
previous 3 months
10. Inability or unwillingness to comply with the provisions of this protocol
11. A history of alcohol or drug abuse
12. A significant illness other than diabetes within 2 weeks prior to first
dosing
13. Known HIV or hepatitis
14. Females who are lactating or pregnant (the possibility of pregnancy must be
excluded by urine βHCG on-site within 24 hours prior to the Diamyd/placebo
treatment)
15. Presence of associated serious disease or condition, including active skin
infections that preclude intralymphatic injection, which in the opinion of the
investigator makes the patient non-eligible for the study
16. Deemed by the investigator not being able to follow instructions and/or
follow the study protocol
Design
Recruitment
Medical products/devices used
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 | EUCTR2017-001861-25-NL |
| ClinicalTrials.gov | NCT03345004 |
| CCMO | NL66896.078.18 |