| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045228 |
| E.1.2 | Term | Type I diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to evaluate the effect of three doses of Diamyd compared to placebo in terms of (1) beta cell function; and (2) glycemic control in adolescents and adults recently diagnosed with T1D, who carry the HLA DR3-DQ2 haplotype and have antibodies against glutamic acid decarboxylase with molecular mass 65 kDa (GAD65). |
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| E.2.2 | Secondary objectives of the trial |
•To compare the effect of Diamyd to placebo treatment with respect to the effects on important diabetes disease management indicators.
Safety Objective:
•To compare the safety of Diamyd to placebo treatment.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional Genomic Sample: DNA Collection and Testing
Objective: to explore potential genetic associations with clinical or biomarker responses. T he objective of the genetic association analyses is to obtain further insights into the mechanisms of action of Diamyd and to identify potential genetic markers of treatment response or AEs, in order to provide an even more individualized treatment approach to each patient in the future.
Patients who agree to participate in the genomic sub-study will be asked to sign a separate genomic sub-study ICF prior to collection of the deoxyribonucleic acid (DNA) sample.
Please refer to Section 10.12 of the protocol for further information.
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| E.3 | Principal inclusion criteria |
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 (V1A).
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 (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 V 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 7day 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:
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.
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| E.4 | Principal exclusion criteria |
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 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.
5. Occurrence of DKA or severe hypoglycemia requiring hospitalization in the period of 90 days prior to Randomization.
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:
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 study 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.
8. 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 study-provided Vitamin D. A patient currently taking Vitamin D at the time of Screening (V1C) must be willing to switch to the study-provided Vitamin D treatment and to administer it per the study requirements.
9. Any clinically significant history of an acute reaction to a vaccine or its constituents (e.g., Alhydrogel).
10. 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.
11. Any acute or chronic skin infection or condition that would preclude intralymphatic injection.
12. 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.
13. 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.
14. Known or suspected acute infection, including COVID-19 or influenza, at the time of Randomization or within 4 weeks prior to Randomization.
15. A history of epilepsy, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles.
16. 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.
17. 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 (V1B) will be permitted.
18. 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.
19. 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, <90 mL/min per 1.73 m or rapidly progressing renal disease.
20. Patients 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).
Refer to protocol other exclusion criteria. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-primary Endpoints
Estimand: (beta cell function)
Treatment: Intralymphatic injections of 4 µg Diamyd or placebo.
Target population: Study participants diagnosed with T1D who carry the HLA
DR3-DQ2 haplotype and have antibodies against GAD65.
Variable: Change from baseline to Month 24 in C-peptide AUCmean 0-120 min during a 2-hour mixed meal tolerance test (MMTT).
Intercurrent event strategy:
1. Study drug discontinuation due to any cause, patient does not withdraw consent: treatment policy strategy.
2. Study drug discontinuation due to any cause, patient withdraws consent: hypothetical strategy.
3. Study drug non-adherence (missing doses) or drug administration error: treatment policy strategy.
4. Prohibited medications and substances, including additional medication (oral or non-insulin injectable therapies) for glycemic control (Sponsor’s Medical Experts will take decision if patient can continue or should be discontinued): hypothetical (if patient is discontinued), or treatment policy (if patient continues in the study) strategy.
Population level summary: The geometric mean ratio (Diamyd/placebo) of the change from baseline in C-peptide AUC mean 0-120 min.
Estimand: (glycemic control)
Treatment: as above.
Target population: as above.
Variable: Change from baseline to Month 24 in HbA1c.
Intercurrent event strategy: as above.
Population level summary: Mean difference in change from baseline. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• MMTT / MMTT-induced C-peptide/ MMTT-induced glucose: At Baseline, D180, D450, EoS
• HbA1c / Fasting plasma glucose: Screening Visit 1B, D0, D30, D60, D180, D360, D450, D540, EoS, ET
where:
D = Day
EoS = End of Study
ET = early termination
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| E.5.2 | Secondary end point(s) |
• Change in time in glycemic target range 3.9 to 10 mmol/L (70 to 180 mg/dL) [evaluated from continuous glucose monitoring (CGM) data] between baseline and Month 24.
• Proportion of patients with IDAA1c ≤9 (partial remission) at Month 24.
• Number of episodes per patient of severe hypoglycemia between baseline and
Month 24.
• Number of episodes per patient of DKA between baseline and Month 24.
Safety Endpoints
• Incidence of treatment-emergent adverse events (TEAEs).
• Incidence of injection site reactions.
• Physical examination findings.
• Vital signs (blood pressure [BP], heart rate [HR], and temperature).
• Clinical laboratory results (chemistry, hematology, and urine). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Continuous glucose monitoring: Screening Visit 1C, D180, D450, EoS
• Adverse events: Baseline, D30, D60, D90, D180, D360, D450, D540, D630, D720, EoS, ET, and at UNS visits.
• Injection site inspection: D0, D30, D60
• Physical examination: Screening Visit 1B, D0, D30, D60, D180, D360, D450, D540, EoS, ET, and at unscheduled (UNS) visits.
• Vital signs: Screening Visits 1B and 1C, D0, D30, D60, D180, D360, D450, D540, EoS, ET, and at UNS visits.
• Clinical chemistry: Screening Visit 1B, D0, D30, D60, D180, D360, D450, EoS, ET
• Hematology: Screening Visit 1B, D0, D30, D60, D180, D360, D450, D540, EoS, ET
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 53 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Czechia |
| Estonia |
| Germany |
| Hungary |
| Netherlands |
| Poland |
| Spain |
| Sweden |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date when the last patient in the study across all sites and regions has returned the continuous glucose monitor (CGM) sensor after 14 days post-End of Study Visit.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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