Evaluation of Diamyd (Recombinant Human Glutamate Decarboxylase 2) and Colecalciferol in Preserving Beta Cell Function in HLA DR3-DQ2 Positive Type 1 Diabetes
- Trial ID
- 2024-513304-33-00
- Protocol
- DIAGNODE-3
- Sponsor
- Diamyd Medical AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III, randomized, double-blind, placebo-controlled, multicenter trial is to evaluate the effect of three doses of **Diamyd** compared to placebo on beta cell function and glycemic control in adolescents and adults recently diagnosed with **Type 1 diabetes mellitus**. The study specifically targets individuals carrying the HLA DR3-DQ2 haplotype, with or without the HLA DR4-DQ8 haplotype, and possessing antibodies against GAD65. This objective is clinically relevant as preserving endogenous beta cell function could potentially improve long-term glycemic control and reduce the need for exogenous insulin in this patient population.
Secondary objectives include:
- Comparing the effect of Diamyd to placebo treatment concerning important diabetes disease management indicators.
- Assessing the safety profile of Diamyd in comparison to placebo treatment.
Participants
The clinical trial involves a total of **50 participants** diagnosed with **Type 1 diabetes mellitus**. The study population comprises both male and female subjects, aged between 12 and 29 years. Participants are required to have been diagnosed with Type 1 diabetes according to the American Diabetes Association classification within six months prior to screening. The trial includes individuals who possess the HLA DR3-DQ2 haplotype and have detectable circulating GAD65 antibodies. Participants must have fasting C-peptide levels of at least 0.12 nmol/L and HbA1c levels between 35 to 80 mmol/mol. The selection process ensures that participants are on a stable insulin basal dose for one month prior to inclusion. The trial population includes adolescents and adults who are considered a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive measures if of childbearing potential. The trial does not specify any particular exclusion criteria beyond the outlined inclusion parameters.
Plans and Procedures
The clinical trial is a **Phase III**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of Diamyd in preserving endogenous beta cell function in adolescents and adults with recently diagnosed **Type 1 diabetes mellitus**. The trial will involve participants who carry the genetic HLA DR3-DQ2 haplotype. The primary objective is to assess the effect of three doses of Diamyd compared to placebo on beta cell function and glycemic control. The trial is expected to run until December 31, 2027, with recruitment having commenced on March 17, 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of Type 1 diabetes within six months, and possession of the HLA DR3-DQ2 haplotype. Following randomization, participants will receive either the investigational drug or placebo. The trial includes multiple follow-up visits to monitor safety and efficacy, with assessments such as C-peptide levels, HbA1c, and continuous glucose monitoring data. The end-of-study visit will occur at Month 24, where final evaluations will be conducted.
The expected length of participant involvement is approximately 24 months. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will ensure that all participants provide informed consent, and for minors, age-appropriate assent and parental consent will be obtained. The study will adhere to rigorous safety monitoring, including the incidence of treatment-emergent adverse events and injection site reactions.
Treatment
The clinical trial involves the administration of **Diamyd**, a **suspension for injection** containing the active substance **glutamate decarboxylase 2, human, recombinant**. This experimental medication is of biological/biotechnological origin and is administered via **intralymphatic use**. The dosing regimen includes a maximum daily dose of 4 µg, with a total maximum dose of 12 µg over a treatment period of 2 weeks. The primary objective of the trial is to evaluate the efficacy of Diamyd in preserving endogenous beta cell function in adolescents and adults with recently diagnosed Type 1 Diabetes who carry the genetic HLA DR3-DQ2 haplotype.
In addition to Diamyd, the trial includes the administration of **Divisun 2000 IE tabletter**, a **tablet** formulation containing the active substance **colecalciferol**. This non-experimental treatment serves as a vitamin supplement and is administered orally. The maximum daily dose is 2000 IU, with the same total dose over a treatment period of 120 days. This treatment is intended to support the overall health of participants during the trial.
The trial also utilizes **Alhydrogel®**, which is categorized as an auxiliary product. However, specific details regarding its pharmaceutical form, active substance, and route of administration are not provided. Alhydrogel® is included in the trial to potentially enhance the immune response to the experimental treatment.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change from baseline to Month 24 in C-peptide AUC mean 0-120 min during a 2-hour Mixed Meal Tolerance Test (MMTT) and the change from baseline to Month 24 in **HbA1c** levels. These endpoints are designed to evaluate the preservation of endogenous beta cell function and glycemic control in participants with recently diagnosed Type 1 Diabetes who carry the HLA DR3-DQ2 haplotype.
Secondary endpoints will further assess efficacy by measuring the change in time within the glycemic target range of 3.9 to 10 mmol/L (70 to 180 mg/dL) using continuous glucose monitoring (CGM) data from baseline to Month 24. Additionally, the proportion of patients achieving an IDAA1c ≤9, indicating partial remission, will be evaluated at Month 24. The trial will also monitor the number of episodes per patient of severe hypoglycemia and diabetic ketoacidosis (DKA) from baseline to Month 24. Safety and tolerability will be assessed through the incidence of treatment-emergent adverse events (TEAEs), injection site reactions, physical examination findings, vital signs, and clinical laboratory results, including chemistry, hematology, and urine tests.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Must be capable of providing written, signed, and dated informed consent; and for patients who are minors, age-appropriate assent (performed according to local regulations) and parent/caregiver consent
- 9(i). Females of childbearing potential (FOCBP) must agree to avoid pregnancy and have a negative pregnancy test performed at the required trial visits. FOCBP must agree to use highly effective contraception, during treatment and, until 90 days after the last administration of trial medication. Birth control methods, which may be considered as highly effective (e.g., a failure rate of less than 1% per year when used consistently and correctly) include: • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o Oral. o Intravaginal. o Transdermal. • Progestogen-only hormonal contraception associated with inhibition of ovulation: o Oral. o Injectable. o Implantable. • Intrauterine device. • Intrauterine hormone-releasing system. • Bilateral tubal occlusion. • Vasectomized partner (vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FOCBP trial patient and that the vasectomized partner has received medical assessment of the surgical success). • Sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient).
- 9(ii). Male patients must agree to remain abstinent from heterosexual sex during treatment and for 90 days after treatment or, if sexually active, to use two effective methods of birth control (e.g., male uses a condom and female uses contraception) during and for 90 days after treatment. Acceptable male contraception is as follows: • Condom (male). • Abstinence from heterosexual intercourse. • Vasectomy. The agreement to remain abstinent or use two effective methods of birth control will be clearly defined in the informed consent; the patient or legally authorized representatives (e.g., parents, caregivers, or legal guardians) must sign this specific section.
- Males and females aged ≥12 and <29 years old at the time of Screening(V1A) . Note: In Germany only male and female adults (18 to <29 years of age) will be enrolled
- Diagnosed with T1D (according to the American Diabetes Association [ADA] classification) ≤6 months at the time of Screening (V1A).
- Possess the HLA DR3-DQ2 haplotype (all patients will be tested; prior genetic testing results will not be accepted).
- Fasting C-peptide ≥0.12 nmol/L (≥0.36 ng/mL) on at least one occasion prior to randomization
- Possess detectable circulating GAD65 antibodies (lowest level of detection defined by the method used by the central laboratory)
- Possess HbA1c levels between 35 to 80 mmol/mol (5.4 to 9.5%) on at least one occasion prior to randomization
- Be on a stable insulin basal dose for one month prior to inclusion with limited fluctuation of daily basal insulin requirement based on investigator's assessment. For example, if the average basal insulin dose/kg/24h over a 7-day period compared to the previous 7day period does not vary more than approximately 20% and/or if the daily basal insulin dose does not vary more than 0.1 U/kg/24h, the dose can be considered stable. Individuals that are diagnosed with T1D according to the ADA classification but are not taking insulin are eligible to participate.
Exclusion Criteria
- Participation in any other trial aimed to influence beta cell function from time of diagnosis of T1D
- Treatment with any (live or inactive) vaccine, including influenza vaccine and Coronavirus Disease 2019 (COVID-19) vaccine, within 4 weeks prior to planned first trial dose of trial drug; or planned treatment with any vaccine up to 4 weeks after the last injection with trial drug
- Any acute or chronic skin infection or condition that would preclude Intralymphatic injection
- Recent (past 12 months) or current treatment with Teplizumab TZIELD® or immunosuppressant therapy, including chronic use of systemic glucocorticoid therapy. Inhaled, topical, and intranasal steroid use is acceptable. Short courses (e.g., ≤5 days) of oral, intra-articular injections or injections of steroids will be permitted during the trial
- Continuous/chronic treatment with prescribed or over-the-counter anti-inflammatory therapies. Short-term use (e.g., <7 days) is permissible, for example to treat a headache or in connection with a fever
- Known or suspected acute infection, including COVID-19 or influenza, at the time of Randomization or within 4 weeks prior to Randomization
- A history of epilepsy, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles
- Known diagnosis of human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection. Patients with previous hepatitis C infection that is now cured may be eligible
- Any clinically significant concomitant medical condition, including but not limited to other autoimmune diseases, cardiovascular, gastrointestinal, hematological, immune, renal including a history of renal transplantation, neurological (including Batten disease), significant diabetes complication, any underlying conditions or receiving treatments that could affect red blood cell turnover or other diseases that in the opinion of the investigator would interfere with trial participation or procedures. Celiac disease or elevated transglutaminase antibody titers is not a reason for exclusion
- History of significant hepatic disease or Screening alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) or aspartate aminotransferase (AST) 3 x ULN and/or total bilirubin >2 x ULN. Patients with documented Gilbert syndrome and total bilirubin level ≥2 x ULN due to unconjugated hyperbilirubinemia, without other hepatic impairment, are permitted
- Estimated glomerular filtration rate (eGFR) calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) for those >18 years old, and by the Schwartz equation for those 12 to 18 years old, <60 mL/min per 1.73 m or rapidly progressing renal disease
- Treatment with any oral or non-insulin injectable anti-diabetic medication or other substance used with the intention to preserve beta cell function (e.g., Verapamil, GABA etc.) within 3 months prior to Randomization.
- Patients diagnosed with hypothyroidism or hyperthyroidism must be on stable treatment for at least 3 months prior to Randomization (with normal free thyroxine [T4] levels if hypothyroid)
- Any clinically significant abnormal findings during Screening, and any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the patient’s safety or ability to complete the trial.
- History of maturity-onset diabetes of the young (MODY)
- Pancreatic surgery, chronic pancreatitis, or other pancreatic disorders that could result in decreased beta cell capacity
- Occurrence of DKA or severe hypoglycemia requiring hospitalization in the period of 90 days prior to Randomization
- Signs or symptoms suggesting very poorly controlled diabetes e.g.,ongoing weight loss, polyuria or polydipsia
- Hematologic condition that would make HbA1c uninterpretable including: a) Hemoglobinopathy, with the exception of sickle cell trait or thalassemia minor; or chronic or recurrent hemolysis. b) Donation of blood or blood products to a blood bank, blood transfusion or participation in a clinical trial requiring withdrawal of >400 mL of blood during the 8 weeks prior to the Screening (V1B) visit. c) Significant iron deficiency anemia. d) Heart malformations or vaso-occlusive crisis (VOC) leading to increased turnover of erythrocytes
- Treatment with marketed or over-the-counter Vitamin D at the time of Screening (V1C) and unwilling to abstain from such medication during the 120 days when the patient will be supplemented with the trial provided Vitamin D. A patient currently taking Vitamin D at the time of Screening (V1C) must be willing to switch to the trial-provided Vitamin D treatment and to administer it per the trial requirements
- Any clinically significant history of an acute reaction to a vaccine or its constituents (e.g.,Alhydrogel)
- History of malignancy not in remission within the last 5 years other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma in situ
- Patients with any mental condition rendering him/her unable to understand the nature, scope and possible consequences of the trial, and/or evidence of poor compliance with medical instructions at Screening or showing non-compliance during the Run-In Period
- A history of alcohol or drug abuse or dependence within the past 12 months based on DSM IV criteria
- Previous treatment with the active substance recombinant human GAD65 trial
- Participation in a clinical trial involving administration of an investigational drug in the past 3 months or 5 half- lives (whichever is longer) prior to first dosing of trial drug or during the trial.
- Females who are breastfeeding, pregnant or plan to become pregnant during the trial
- Patients who in the opinion of the investigator will not be able to follow instructions and/or follow the trial procedures or patients that are unwilling or unable to comply with the provisions of this protocol
- An employee or immediate family member of an employee of Diamyd Medical AB
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 17 Mar 2022 | 28 |
 Estonia | Not Recruiting | 17 Mar 2022 | 18 |
 Germany | Not Recruiting | 17 Mar 2022 | 18 |
 Hungary | Not Recruiting | 17 Mar 2022 | 22 |
 The Netherlands | Not Recruiting | 17 Mar 2022 | — |
 Poland | Not Recruiting | 17 Mar 2022 | 60 |
 Spain | Not Recruiting | 17 Mar 2022 | 88 |
 Sweden | Not Recruiting | 17 Mar 2022 | 24 |
| Netherlands | — | — | 22 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Divisun 2000 IE tabletter | Other | TABLETTER | ORAL USE | 2000 | 120 | PRD3532534 |
Alhydrogel® | Placebo | N/A | — | — | — | N/A |
Diamyd | Test | SUSPENSION FOR INJECTION | INTRALYMPHATIC USE | 4 | 2 | PRD221979 |