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A Phase III Study to Investigate if the Study Drug Diamyd Can Preserve Insulin Production and Improve Glycemic Control in Patients Newly Diagnosed With Type 1 Diabetes

Recruiting
12 - 28 years of age
Both
Phase 3

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Overview

The objective of DIAGNODE-3 is to evaluate the efficacy and safety of three intranodal injections of 4 μg of Diamyd compared to placebo, along with oral Vitamin D supplementation, to preserve endogenous beta cell function and influence glycemic parameters in adolescent and adults recently diagnosed with T1D carrying the HLA DR3-DQ2 haplotype.

Description

The study is a 2-arm, randomized, double-blind, placebo-controlled, multicenter, clinical trial. Patients will have the HLA genotyping performed at the first Screening visit (Visit 1A). If the results indicate the patient is carrying the HLA DR3-DQ2 haplotype, then the patient will attend the second Screening visit (Visit 1B) to perform the remaining screening procedures. Eligible patients will receive injections of Diamyd/placebo into an inguinal lymph gland at three occasions, with one month intervals along with oral Vitamin D supplementation. All patients will continue to receive intensive insulin treatment from their personal physicians during the whole study period. Patients will be followed in a blinded manner for a total of 24 months.

Eligibility

Inclusion Criteria:

        Patients are eligible to be included in this study only if all of the following criteria
        apply:
          1. 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.
          2. Males and females aged ≥12 and <29 years old at the time of Screening.
          3. Diagnosed with T1D (according to the American Diabetes Association [ADA]
             classification) ≤6 months at the time of Screening.
          4. Possess the HLA DR3-DQ2 haplotype (all patients will be tested; prior genetic testing
             results will not be accepted).
          5. Fasting C-peptide ≥0.12 nmol/L (≥0.36 ng/mL) on at least one occasion (maximum two
             tests on different days during the Screening period).
             (US ONLY): Fasting C-peptide ≥0.12 - ≤1.5 nmol/L (≥0.36 - ≤4.5 ng/mL) on at least one
             occasion (maximum two tests on different days during the Screening period).
          6. Possess detectable circulating GAD65 antibodies (lowest level of detection defined by
             the method used by the central laboratory).
          7. Possess HbA1c levels between 35 to 80 mmol/mol (5.4 to 9.5%) on at least one occasion
             prior to randomization (maximum one additional test within one month from Visit 1B).
          8. Be on a stable insulin dose or insulin dosing regimen for one month prior to inclusion
             with limited fluctuation of daily insulin requirement based on investigator's
             assessment. For example, if the average insulin dose/kg/24h over a 7-day period
             compared to the previous 7-day period does not vary more than approximately 15% and/or
             if the daily 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.
          9. i. Females of childbearing potential (FOCBP) must agree to avoid pregnancy and have a
             negative pregnancy test performed at the required study visits.
        FOCBP must agree to use highly effective contraception, during treatment and, until 90 days
        after the last administration of study 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:
               -  Oral.
               -  Intravaginal.
               -  Transdermal.
          -  Progestogen-only hormonal contraception associated with inhibition of ovulation:
               -  Oral.
               -  Injectable.
               -  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.
        Exclusion Criteria:
        Patients are not eligible to be included in this study if any of the following criteria
        apply:
          1. Participation in any other trial aimed to influence beta cell function from time of
             diagnosis of T1D.
          2. Treatment with any oral or non-insulin injectable anti-diabetic medication within 3
             months prior to Screening.
          3. History of maturity-onset diabetes of the young (MODY).
          4. Pancreatic surgery, chronic pancreatitis, or other pancreatic disorders that could
             result in decreased beta cell capacity (e.g., pancreatogenous diabetes).
          5. History of DKA or severe hypoglycemia requiring hospitalization within one month
             before Screening, or severe episodes of hypoglycemia requiring third party assistance
             within one month before Screening.
             (US ONLY) Occurrence of DKA or severe hypoglycemia requiring hospitalization in the
             period of 90 days prior to Randomization (Visit 2).
          6. Signs or symptoms suggesting very poorly controlled diabetes e.g., ongoing weight
             loss, polyuria or polydipsia.
          7. Hematologic condition that would make HbA1c uninterpretable including:
               1. Hemoglobinopathy, with the exception of sickle cell trait or thalassemia minor;
                  or chronic or recurrent hemolysis.
               2. Donation of blood or blood products to a blood bank, blood transfusion or
                  participation in a clinical study requiring withdrawal of >400 mL of blood during
                  the 8 weeks prior to the Screening visit.
               3. Significant iron deficiency anemia.
               4. Heart malformations or vaso-occlusive crisis (VOC) leading to increased turnover
                  of erythrocytes.
          8. (US ONLY) Abnormal hematology results at the time of Screening, specifically any of
             the following: white blood cells: Female 12-18 y < 5.5 x 109/L or >9.3 x 109/L, Male
             12-18 y < 5.2 x 109/L or >9.7 x 109/L, Adults >18 y < 3.5 x 109/L or >11.1 x 109/L;
             platelets: Female 12-18 y < 192 x 109/L or > 307 x 109/L, Male 12-18 y < 180 x 109/L
             or > 299 x 109/L, Adults >18 y < 150 x 109/L or >400 x 109/L; hemoglobin: Female 12-18
             y < 11.3 g/dL or > 13.4 g/dL, Male 12-18 y < 11 g/dL or >14.3 g/dL, Female >18 y <
             11.5 g/dL or > 15.5 g/dL, Male >18 y < 13.2 g/dL or > 17 g/dL.
          9. Treatment with marketed or over-the-counter Vitamin D at the time of Screening and
             unwilling to abstain from such medication during the 120 days when the patient will be
             supplemented with the study-provided Vitamin D. A patient currently taking Vitamin D
             at the time of Screening must be willing to switch to the study-provided Vitamin D
             treatment and to administer it per the study requirements.
         10. (US ONLY) History of hyperparathyroidism, hypercalcemia and/or nephrolithiasis, unless
             appropriately treated, or any other contraindication to use of Vitamin D.
         11. Any clinically significant history of an acute reaction to a vaccine or its
             constituents (e.g., Alhydrogel).
         12. Treatment with any (live or inactive) vaccine, including influenza vaccine and
             Coronavirus Disease 2019 (COVID-19) vaccine, within 4 weeks prior to planned first
             study dose of study drug; or planned treatment with any vaccine up to 4 weeks after
             the last injection with study drug.
         13. Any acute or chronic skin infection or condition that would preclude intralymphatic
             injection.
         14. Recent (past 12 months) or current treatment with immunosuppressant therapy, including
             chronic use of glucocorticoid therapy. Inhaled, topical, and intranasal steroid use is
             acceptable. Short courses (e.g., ≤5 days) of oral or intra-articular injections of
             steroids will be permitted on trial.
         15. 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.
         16. Known or suspected acute infection, including COVID-19 or influenza, at the time of
             Screening or within 2 weeks prior to Screening. After confirmed recent COVID-19
             infection, a negative polymerase chain reaction test will be required before
             randomization.
         17. A history of epilepsy, head trauma or cerebrovascular accident, or clinical features
             of continuous motor unit activity in proximal muscles.
         18. 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.
         19. 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 with adequate diet before diagnosis or discovered by increased
             autoantibodies at Screening will be permitted.
             (US ONLY) Any clinically significant concomitant medical condition, including but not
             limited to other autoimmune or immune deficiency diseases (e.g., sarcoidosis,
             rheumatoid arthritis, moderate-to-severe psoriasis, inflammatory bowel disease, and
             other autoimmune conditions that may require treatment with TNF-alpha inhibitors or
             other biologics), gastrointestinal, hematological, or renal diseases including a
             history of any organ transplant (including renal transplantation and islet
             transplantation), neurological disease (including Batten disease); significant
             diabetes complication; a history of adrenal insufficiency; any underlying conditions
             or receiving treatments that could affect red blood cell turnover or other diseases
             that interfere with trial participation or procedures. Celiac disease with adequate
             diet before diagnosis or discovered by increased autoantibodies at Screening will be
             permitted, as well as autoimmune thyroid disease under certain conditions (see
             Exclusion Criterion #23).
         20. Significant cardiovascular disease (including inadequately controlled hypertension
             [resting blood pressure >140/90 mmHg despite treatment], history of myocardial
             infarction, angina, use of anti-anginal medicines [e.g., nitroglycerin], or abnormal
             cardiac stress test.
         21. 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.
         22. Estimated glomerular filtration rate (eGFR) calculated by Chronic Kidney Disease
             Epidemiology Collaboration (CKD-Epi) for those >18 years, or by the Schwartz equation
             for those 12 to 18 years old, <90 mL/min per 1.73 m or rapidly progressing renal
             disease.
         23. Patients with hypothyroidism or hyperthyroidism must be on stable treatment for at
             least 3 months prior to Screening (with normal free thyroxine [T4] levels if
             hypothyroid).
             (US ONLY) Patients with hypothyroidism or hyperthyroidism must be on stable treatment
             for at least 3 months prior to Screening (with normal free thyroxine [T4] levels if
             hypothyroid). A thyroid-stimulating hormone (TSH) level > 1.5 times the ULN at
             Screening is an exclusion criterion.
         24. 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.
             (US ONLY) 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. This includes
             anticipated major surgery during the duration of the trial, which could interfere with
             participation in the trial.
         25. 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.
         26. 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.
         27. A history of alcohol or drug abuse or dependence within the past 12 months based on
             DSM IV criteria.
         28. Current or previous participation in a trial of Diamyd.
         29. 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
             study drug or during the trial.
         30. Females who are breastfeeding, pregnant or plan to become pregnant during the trial.
         31. Patients who in the opinion of the investigator will not be able to follow
             instructions and/or follow the study procedures or patients that are unwilling or
             unable to comply with the provisions of this protocol.
         32. An employee or immediate family member of an employee of Diamyd Medical AB.
         33. (US ONLY) For subjects aged 18 years and older, a body mass index (BMI) ≥25 kg/m2 or
             ≤18.5 kg/m2; for subject aged under 18 years BMI ≥85th percentile or ≤5th percentile
             for age and sex according to the US Centre for Disease Control and Prevention.

Study details

Type 1 Diabetes Mellitus

NCT05018585

Diamyd Medical AB

24 June 2024

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