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

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 forpatients who are minors, age-appropriate assent (performed according to localregulations) 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 genetictesting results will not be accepted).

5. Fasting C-peptide ≥0.12 nmol/L (≥0.36 ng/mL) on at least one occasion prior torandomization.

(US ONLY): Fasting C-peptide ≥0.12 - ≤1.5 nmol/L (≥0.36 - ≤4.5 ng/mL) on at leastone occasion prior to randomization.

6. Possess detectable circulating GAD65 antibodies (lowest level of detection definedby 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 oneoccasion prior to randomization.

8. Be on a stable basal insulin dose for one month prior to inclusion with limitedfluctuation 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 comparedto the previous 7-day period does not vary more than approximately 20% and/or if thedaily basal insulin dose does not vary more than 0.1 U/kg/24h, the dose can beconsidered stable. Individuals that are diagnosed with T1D according to the ADAclassification but are not taking insulin are eligible to participate.

9. i. Females of childbearing potential (FOCBP) must agree to avoid pregnancy and havea 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 associatedwith 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 controlmethod provided that partner is the sole sexual partner of the FOCBP trial patientand that the vasectomized partner has received medical assessment of the surgicalsuccess).

• Sexual abstinence (sexual abstinence is considered a highly effective method only ifdefined as refraining from heterosexual intercourse during the entire period of riskassociated with the study drugs. The reliability of sexual abstinence needs to beevaluated in relation to the duration of the clinical trial and the preferred andusual lifestyle of the patient).

9. ii. Male patients must agree to remain abstinent from heterosexual sex duringtreatment and for 90 days after treatment or, if sexually active, to use twoeffective methods of birth control (e.g., male uses a condom and female usescontraception) during and for 90 days after treatment. Acceptable malecontraception is as follows:

• Condom (male).

• Abstinence from heterosexual intercourse.

• Vasectomy. The agreement to remain abstinent or use two effective methods of birthcontrol will be clearly defined in the informed consent; the patient or legallyauthorized representatives (e.g., parents, caregivers, or legal guardians) must signthis 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 ofdiagnosis of T1D.

2. Treatment with any oral or non-insulin injectable anti-diabetic medication or othersubstance 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 couldresult 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 weightloss, polyuria or polydipsia.

7. Hematologic condition that would make HbA1c uninterpretable including:

8. Hemoglobinopathy, with the exception of sickle cell trait or thalassemia minor;or chronic or recurrent hemolysis.

9. Donation of blood or blood products to a blood bank, blood transfusion orparticipation in a clinical study requiring withdrawal of >400 mL of bloodduring the 8 weeks prior to the Screening visit.

10. Significant iron deficiency anemia.

11. Heart malformations or vaso-occlusive crisis (VOC) leading to increasedturnover of erythrocytes.

12. (US ONLY) Clinically significant abnormal hematology results at the time ofScreening, 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

13. 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 patientwill be supplemented with the trial-provided Vitamin D. A patient currently takingVitamin D at the time of Screening (V1C) must be willing to switch to thetrial-provided Vitamin D treatment and to administer it per the trial requirements.

14. (US ONLY) History of hyperparathyroidism, hypercalcemia and/or nephrolithiasis,unless appropriately treated, or any other contraindication to use of Vitamin D.

15. Any clinically significant history of an acute reaction to a vaccine or itsconstituents (e.g., Alhydrogel).

16. Treatment with any (live or inactive) vaccine, including influenza vaccine andCoronavirus Disease 2019 (COVID-19) vaccine, within 4 weeks prior to planned firsttrial dose of trial drug; or planned treatment with any vaccine up to 4 weeks afterthe last injection with trial drug.

17. Any acute or chronic skin infection or condition that would preclude intralymphaticinjection.

18. Recent (past 12 months) or current treatment with Teplizumab (TZIELD®) or withimmunosuppressant therapy, including chronic use of systemic glucocorticoid therapy.Inhaled, topical, and intranasal steroid use is acceptable. Short courses (e.g., ≤5days) of oral, intra-articular injections or injections of steroids will bepermitted during the trial.

19. Continuous/chronic treatment with prescribed or over-the-counter anti-inflammatorytherapies. Short-term use (e.g., <7 days) is permissible, for example to treat aheadache or in connection with a fever.

20. Known or suspected acute infection, including COVID-19 or influenza, at the time ofRandomization or within 4 weeks prior to Randomization.

21. A history of epilepsy, head trauma or cerebrovascular accident, or clinical featuresof continuous motor unit activity in proximal muscles.

22. Known diagnosis of human immunodeficiency virus (HIV), hepatitis B or hepatitis Cinfection. Patients with previous hepatitis C infection that is now cured may beeligible.

23. Any clinically significant concomitant medical condition, including but not limitedto other autoimmune diseases, cardiovascular, gastrointestinal, hematological,immune, renal including a history of renal transplantation, neurological (includingBatten disease), significant diabetes complication, any underlying conditions orreceiving treatments that could affect red blood cell turnover or other diseasesthat in the opinion of the investigator would interfere with trial participation orprocedures. Celiac disease or elevated transglutaminase antibody titers is not areason for exclusion.

(US ONLY) Any clinically significant concomitant medical condition, including butnot limited to other autoimmune or immune deficiency diseases (e.g., sarcoidosis,rheumatoid arthritis, moderate-to-severe psoriasis, inflammatory bowel disease, andother autoimmune conditions that may require treatment with TNF-alpha inhibitors orother biologics), gastrointestinal, hematological, or renal diseases including ahistory of any organ transplant (including renal transplantation and islettransplantation), neurological disease (including Batten disease); significantdiabetes complication; a history of adrenal insufficiency; any underlying conditionsor receiving treatments that could affect red blood cell turnover or other diseasesthat interfere with trial participation or procedures. Celiac disease or elevatedtransglutaminase antibody titers is not a reason for exclusion, as well asautoimmune thyroid disease under certain conditions (see Exclusion Criterion #23).

20. (US ONLY) Significant cardiovascular disease (including inadequately controlledhypertension [resting blood pressure >140/90 mmHg despite treatment], history ofmyocardial 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 ULNand/or total bilirubin >2 x ULN. Patients with documented Gilbert syndrome and totalbilirubin level ≥2 x ULN due to unconjugated hyperbilirubinemia, without otherhepatic impairment, are permitted.

22. Estimated glomerular filtration rate (eGFR) calculated by Chronic Kidney DiseaseEpidemiology Collaboration (CKD-Epi) for those >18 years, or by the Schwartzequation for those 12 to 18 years old, <60 mL/min per 1.73 m or rapidly progressingrenal disease.

23. Patients diagnosed with hypothyroidism or hyperthyroidism must be on stabletreatment 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 onstable treatment for at least 3 months prior to Randomization (with normal freethyroxine [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 medicalcondition(s) or laboratory findings that, in the opinion of the investigator, mightjeopardize the patient's safety or ability to complete the trial.

(US ONLY) Any clinically significant abnormal findings during Screening, and anyother medical condition(s) or laboratory findings that, in the opinion of theinvestigator, might jeopardize the patient's safety or ability to complete thetrial. 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 adequatelytreated basal cell or squamous cell skin cancer or cervical carcinoma in situ.

26. Patients with any mental condition rendering him/her unable to understand thenature, scope and possible consequences of the trial, and/or evidence of poorcompliance with medical instructions at Screening or showing non-compliance duringthe Run-In Period.

27. A history of alcohol or drug abuse or dependence within the past 12 months based onDSM IV criteria.

28. Previous treatment with the active substance recombinant human GAD65.

29. Participation in a clinical trial involving administration of an investigationaldrug in the past 3 months or 5 half-lives (whichever is longer) prior to firstdosing 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 followinstructions and/or follow the trial procedures or patients that are unwilling orunable 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 ≤5thpercentile for age and sex according to the US Centre for Disease Control andPrevention at V1B. (For subjects aged 18 years and older with a BMI ≥25 to ≤30kg/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, independentendocrinologist is required prior to randomization.)