Clinical trial NCT05018585: 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
Official title: A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter Trial to Evaluate the Efficacy and Safety of Diamyd® to Preserve Endogenous Beta Cell Function in Adolescents and Adults With Recently Diagnosed Type 1 Diabetes, Carrying the Genetic HLA DR3-DQ2 Haplotype
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Type 1 Diabetes Mellitus
Keywords: Diabetes Mellitus
residual beta cell function
HLA DR3-DQ2
Diabetes Mellitus, Type 1
Autoimmune Diseases
Metabolic Disease
Autoimmune Diabetes
Vitamin D
Immune System Diseases
Insulin Dependent Diabetes
rhGAD65
GAD65
GAD-alum
residual c-peptide
T1D
recent-onset T1D
Type 1 Diabetes
HLA
Diamyd
Diabetes
Newly Diagnosed
New onset
DIAGNODE-3
GAD
Diamyd GAD
Intralymphatic injections
Diabetes immunotherapy
Immunotherapy
Antigen-specific
Lead sponsor: Diamyd Medical AB
Sponsor class: INDUSTRY
First posted: 2021-08-24
Enrollment: 330
Sex: ALL
Minimum age (years): 12
Maximum age (years): 28
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study is a 2-arm, randomized, double-blind, placebo-controlled, multicenter, clinical trial.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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 criteria: 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 (V1A).
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 prior to randomization.

   (US ONLY): Fasting C-peptide ≥0.12 - ≤1.5 nmol/L (≥0.36 - ≤4.5 ng/mL) on at least one occasion prior to randomization.
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.
8. Be on a stable basal insulin 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 7-day 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.
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 or other substance used with the intention to preserve beta cell function (e.g., Verapamil, GABA etc.) within 3 months prior to Randomization.
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. 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) Clinically significant abnormal hematology results at the time of Screening, specifically any of the following: white blood cells: \< 3.5 x 109/L or \>15 x 109/L; platelets: \<124 x 109/ L hemoglobin: \<10.5 g/dL
9. 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.
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 trial dose of trial drug; or planned treatment with any vaccine up to 4 weeks after the last injection with trial drug.
13. Any acute or chronic skin infection or condition that would preclude intralymphatic injection.
14. Recent (past 12 months) or current treatment with Teplizumab (TZIELD®) or with 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.
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 Randomization or within 4 weeks prior to 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 or elevated transglutaminase antibody titers is not a reason for exclusion.

    (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 or elevated transglutaminase antibody titers is not a reason for exclusion, as well as autoimmune thyroid disease under certain conditions (see Exclusion Criterion #23).
20. (US ONLY) 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, \<60 mL/min per 1.73 m or rapidly progressing renal disease.
23. 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).

    (US ONLY) 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). A thyroid-stimulating hormone (TSH) level \> 1.5 times the ULN at Screening (V1B) 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. Previous treatment with the active substance recombinant human GAD65.
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 trial 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 trial 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) ≥30 kg/m2 or ≤18.5 kg/m2; for subjects aged under 18 years BMI ≥95th percentile or ≤5th percentile for age and sex according to the US Centre for Disease Control and Prevention at V1B. (For subjects aged 18 years and older with a BMI ≥25 to ≤30 kg/m2, and for subjects aged under 18 years with a BMI ≥85th to ≤95th percentile, re-confirmation of Type 1 Diabetes diagnoses by an external, independent endocrinologist is required prior to randomization.)

Primary outcomes:
measure: Beta cell function
timeFrame: Baseline to 24 months
measure: Glycemic control
timeFrame: Baseline to 24 months
Secondary outcomes:
measure: Change in time in glycemic target range 3.9 to 10 mmol/L (70 to 180 mg/dL) between baseline and Month 24.
timeFrame: Baseline and 24 months
measure: Proportion of patients with insulin dose-adjusted HbA1c ≤9 at Month 24.
timeFrame: 24 Months
measure: Number of episodes per patient of severe hypoglycemia between baseline and Month 24.
timeFrame: Baseline and 24 months
measure: Number of episodes per patient of diabetic ketoacidosis between baseline and Month 24.
timeFrame: Baseline and 24 months
Other outcomes:
Locations:
city: Newport Beach
country: United States
facility: Mary and Dick Allen Diabetes Center at Hoag Hospital
state: California
city: Palo Alto
country: United States
facility: Stanford University School of Medicine Center for Academic Medicine
state: California
city: San Diego
country: United States
facility: UCSD/ Rady Children's Hospital
state: California
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus, Barbara Davis Center for Childhood Diabetes
state: Colorado
city: Miami
country: United States
facility: Diabetes Research Institute (DRI)-University of Miami Leonard M. Miller School of Medicine (UMMSM)
state: Florida
city: Idaho Falls
country: United States
facility: Rocky Mountain Diabetes and Osteoporosis Center
state: Idaho
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: St. Louis
country: United States
facility: Washington University Diabetes Center at Barnes Jewish Hospital
state: Missouri
city: New York
country: United States
facility: Hassenfeld Children&#39;s Hospital at NYU Langone Health, Pediatric Diabetes Center
state: New York
city: Amarillo
country: United States
facility: Amarillo Medical Specialists
state: Texas
city: San Antonio
country: United States
facility: Diabetes &amp; Glandular Disease Clinic
state: Texas
city: Jihlava
country: Czechia
facility: Nemocnice Jihlava, příspěvková organizace
city: Prague
country: Czechia
facility: Institut klinické a experimentální medicíny
city: Prague
country: Czechia
facility: Fakultní nemocnice v Motole
city: Ústí Nad Labem
country: Czechia
facility: Krajská zdravotní, a.s. - Masarykova nemocnice v Ústí nad Labem, o.z.
city: Pärnu
country: Estonia
facility: Liina Viitas OÜ
city: Tallinn
country: Estonia
facility: North-Estonian Regional Hospital
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Tartu
country: Estonia
facility: Tartu University Hospital, Children's Clinic
city: Berlin
country: Germany
facility: Diabetespraxis Dr. Braun
city: Dortmund
country: Germany
facility: Diabetologische Schwerpunktpraxis Dres. Klaus
city: Duisburg
country: Germany
facility: DZDM - Diabeteszentrum Duisburg Mitte
city: Giessen
country: Germany
facility: Justus-Liebig-Universität Gießen
city: Budapest
country: Hungary
facility: Óbudai Egészségügyi Centrum
city: Budapest
country: Hungary
facility: Heim Pál Országos Gyermekgyógyászati Intézet, Diabetológia
city: Budapest
country: Hungary
facility: Észak-Budai Szent János Centrumkórház, Kútvölgyi Kórház, Belgyógyászat
city: Nyíregyháza
country: Hungary
facility: Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi, Oktatókórház, Jósa András Oktatókórház, Gyermekosztály
city: Szombathely
country: Hungary
facility: Markusovszky Egyetemi Oktatókórház, Diabetológiai Szakrendelés
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, Academic Medical Center (AMC)
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
city: Hoogeveen
country: Netherlands
facility: Bethesda Diabetes Research Center te Hoogeveen
city: Leiden
country: Netherlands
facility: Dept. of Nephrology / Dept. of Endocrinology, Leiden University Medical Center (LUMC)
city: Nijmegen
country: Netherlands
facility: Vivendia
city: Rotterdam
country: Netherlands
facility: Diabeter Nederland te Rotterdam
city: Bialystok
country: Poland
facility: Uniwersytecki Dziecięcy Szpital Kliniczny im. L. Zamenhofa w Białymstoku, Klinika Pediatrii, Endokrynologii, Diabetologii z Pododdziałem Kardiologii
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne, Klinika Pediatrii, Diabetologii i Endokrynologii
city: Kraków
country: Poland
facility: SP ZOZ Szpital Uniwersytecki w Krakowie, Oddział Kliniczny Chorób Metabolicznych i Diabetologii
city: Lublin
country: Poland
facility: NZOZ Przychodnia Specjalistyczna Medica
city: Rzeszów
country: Poland
facility: Kliniczny Szpital Wojewódzki nr 2 im. Św. Jadwigi Królowej w Rzeszowie, II Klinika Pediatrii, Endokrynologii i Diabetologii Dziecięcej
city: Warsaw
country: Poland
facility: Instytut Diabetologii Sp. z o.o
city: Warsaw
country: Poland
facility: Panstwowy Instytut Medyczny MSWiA Klinika Chorob Wewnetrznych, Endokrynologii i Diabetologii
city: Warsaw
country: Poland
facility: Instytut Pomnik - Centrum Zdrowia Dziecka (IPCZD) Oddział Diabetologii
city: Barakaldo
country: Spain
facility: Hospital De Cruces
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de Sant Joan de Déu - Esplugues De Llobregat, Barcelona
city: Girona
country: Spain
facility: Hospital Universitari de Girona Dr. Josep Trueta
city: Las Palmas
country: Spain
facility: Complejo Hospitalario Insular de Gran Canaria
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Málaga
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Malmö
country: Sweden
facility: Skånes universitetssjukhus
state: Skåne
city: Stockholm
country: Sweden
facility: Akademiskt Specialistcentrum, Centrum for Diabetes
state: Stockholms län
city: Umeå
country: Sweden
facility: Barn-och Ungdomscentrum Västerbotten, Norrlands Universitetssjukhus
state: Västerbotten
city: Linköping
country: Sweden
facility: H.K.H Kronprinsessan Victorias Barn-och Ungdomssjukhus, Universitetssjukhuset i Linköping
state: Östergötland
Study officials:
affiliation: Crown Princess Victoria Children´s Hospital and Linköping University
name: Johnny Ludvigsson, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ludvigsson J, Eriksson L, Nowak C, Teixeira PF, Widman M, Lindqvist A, Casas R, Lind M, Hannelius U. Phase III, randomised, double-blind, placebo-controlled, multicentre trial to evaluate the efficacy and safety of rhGAD65 to preserve endogenous beta cell function in adolescents and adults with recently diagnosed type 1 diabetes, carrying the genetic HLA DR3-DQ2 haplotype: the DIAGNODE-3 study protocol. BMJ Open. 2022 Oct 31;12(10):e061776. doi: 10.1136/bmjopen-2022-061776.