Study of Safety and Efficacy of CFZ533 in Type 1 Diabetes Pediatric and Young Adult Subjects

Inclusion criteria

• Written informed consent, and if needed assent from the child on the trial, must be obtained before any assessment is performed.
• Males and females aged between 12 and 21 years (inclusive, and enrolled in stages) at screening.
• Body weight range from 30 to 125 kg (inclusive).
• Evidence of one or more type 1 diabetes autoantibody(ies) against: glutamic acid decarboxylase (anti-GAD), protein tyrosine, phosphatase-like protein (anti-IA-2); zinc transporter 8 (anti-ZnT8); islet cell (cytoplasmic) (anti-ICA) at screening or baseline in the central laboratory OR historical clinical record of one or more of the T1DM diabetes autoantibodies. As part of the historical record insulin autoantibodies (IAA) may have been used as part of the autoantibody panel but the blood sample must have been obtained prior to or within one week of starting exogenous insulin treatment.
• Able to receive first dose of study drug within 56 days of diagnosis of T1DM (which may be extended to within 100 days of diagnosis in the event a screening assessment needs to be confirmed or vaccine administered).
• Peak stimulated C-peptide levels ≥0.2 nmol/L (0.6 ng/mL) following standard liquid mixed meal tolerance test (MMTT), to be conducted when the subject is metabolically stable, at least 2 weeks from diagnosis and within 56 days prior to randomization (or within 100 days of diagnosis in the event a screening assessment needs to be confirmed or vaccine is required).
• Study participants are to complete all recommended immunizations with live, attenuated vaccine at least eight weeks prior and killed, inactivated vaccine at least two weeks prior to first dose with study drug and in accordance with local immunization guidelines. In the event a subject has not had all vaccinations recommended according to local guidance, the screening period may be extended beyond 56 days to allow these vaccinations to be administered, but first dose of study drug must be administered within 100 days of diagnosis of T1DM.
• Must be willing to comply with the standard of care for diabetes management.
• A negative pregnancy test at screening is required for all sexually mature female subjects prior to participation in the study.
• Subject and/or guardian must be able to communicate well with the investigator, to understand and comply with the requirements of the study.

Exclusion criteria

• Diabetes forms other than auto immune type 1 such as maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of the adult (LADA), acquired diabetes (secondary to medications or surgery), type 2 diabetes by judgement of the investigator.
• Diabetic ketoacidosis within 2 weeks of the baseline MMTT test.
• Polyglandular auto immune disease, Addison's disease, pernicious anemia, celiac sprue. Note: Investigators are not mandated to test for Celiac disease (also known as Sprue). Subjects suspected of having Celiac disease should be tested for the presence of disease, as part of good medical care, as treatment would differ. Treated, stable Hashimoto's thyroiditis is not exclusionary.
• Any of the following abnormal laboratory values at screening: total white blood cell count (WBC) outside the range of 1,500-15,000/mm3 (1.5-15.0 x 109/L), neutrophil count (<1500/mm3) (<1.5 X 109 / L), lymphocyte count <500/mm3 (<0.5 X 109 / L), hemoglobin (Hgb) <8.0 g/dL, platelets <100,000/mm3 (<100 x 109/L) 5. History of immunodeficiency disorders, such as HyperIgM syndrome; history of recurrent infections suggestive of immunodeficiency disorders.

• History of or active coagulation disorder with increased thromboembolic risk; a PTT and PT/ INR below lower limit of normal prior to inclusion.

• Tuberculosis infection assessed by positive QuantiFERON TB-Gold test (QFT) at screening. Subjects with a positive QFT test may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the subject has no evidence of active tuberculosis. If presence of latent tuberculosis is established, then anti tuberculosis treatment must have been initiated and maintained according to local country guidelines.

• Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface antigen (HBsAg) test, at screening, excludes a subject. Subjects with a positive HCV antibody test should have HCV RNA levels measured. Subjects with positive (detectable) HCV RNA should be excluded.

• Positive human immune virus HIV test (ELISA and Western Blot) at screening. 10. Evidence of EBV, CMV, HSV, and/or SARS-CoV-2 infection by viral load above laboratory upper limit of normal or only positive IgM serology in the absence of positive IgG at screening. Rescreening is permitted in persistently asymptomatic or postsymptomatic subjects, but study drug must be able to be administered within 100 days of diagnosis of T1D and viral load must be negative and IgG titers positive.

• Major dental work (e.g. tooth extractions or dental surgery with access to dental pulp) within 8 days of first dose; febrile illness within 48 hrs of first dose.

• Use of other investigational drugs or use of immunosuppressive agents at the time of enrollment, or within 5 half-lives of enrollment, or until the expected PD effect has returned to baseline, whichever is longer; or longer if required by local regulations.

• History of multiple and recurring allergies or allergy to the investigational compound/compound class being used in this study. Multiple and recurring allergies refer to known allergies to the investigational compound, to immunoglobulin based therapies, or to multiple drug classes. Dust mites, hay fever, and similar environmental allergies are not exclusionary.

• History of severe hypersensitivity reaction or anaphylaxis to biological agents, e.g. human monoclonal antibody.

• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within 5 years of screening, regardless of whether there is evidence of local recurrence or metastases.

• Active serious psychiatric disorders (diagnosed or treated by a psychiatrist), such as eating disorders and psychosis or history thereof.

• Any complicating medical issues or clinically abnormal laboratory results that may cause an increased safety risk to the subject as judged by the investigator.

• Ongoing, and up to 2 weeks prior to screening, use of medications that may affect glucose control (e.g, systemic steroids, thiazides, beta blockers). A short course of oral steroids <10 days if medically required is permissible with sponsor notification.

• History of drug abuse, nicotine or harmful alcohol use within 12 months prior to first dose, or evidence (as determined by the investigators) of such abuse at screening. For example, harmful alcohol use in adults is defined as five or more drinks per day for 5 or more days in the past 30 days. Harmful alcohol use by adolescents (age 13-18 years) is to be determined by the investigator, based on local culture and laws. Harmful cannabinoid use is difficult to define universally and the determination of abuse will be made by the Investigator based on local culture and law.

• Taking medications prohibited by the protocol 21. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.

• Women of child-bearing potential, defined as all women, who are sexually active, physiologically capable of becoming pregnant (e.g. menstruating), unless they are using highly effective methods of contraception during dosing and for 14 weeks after stopping the investigational drug. Highly effective contraception methods include:

• Total abstinence from heterosexual intercourse (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to first dose. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male sterilization in the sexual partner of female study participant (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
• In case of use of oral contraception, women should be stable on the same pill for a minimum of 3 months prior to first dose.