ZP4207(Dasiglucagon) Administered to T1D Patients to Assess the PK and PD Compared to Marketed Glucagon

Randomised, Sequential, Cross-over Trial Assessing PK and PD Responses After Micro-doses of ZP4207 Administered s.c. to Patients With T1D Under eu- and Hypoglycemic Conditions and With Reference to Freshly Reconstituted Lyophilized Glucagon

The trial is a single-centre, randomised, sequential, cross-over trial assessing pharmacokinetic and pharmacodynamic responses after micro-doses of ZP4207 (dasiglucagon*) administered subcutaneously to patients with type 1 diabetes mellitus under euglycaemic and hypoglycaemic conditions and compared to marketed glucagon.

*dasiglucagon is the proposed International Nonproprietary Name (pINN) for ZP4207

Seventeen (17) adult patients with T1DM treated with continuous subcutaneous insulin infusion (insulin pumps, CSII) will be randomized and take part at four dosing visits. The dosing visits are separated by 3-7 days. For the three lowest dose levels (0.03 mg, 0.08 mg, and 0.2 mg) the patients will receive two doses of ZP4207(dasiglucagon) (the first at euglycaemic and the second at hypoglycaemic conditions) and one dose of glucagon at euglycaemic conditions at visit 2-4. The first two dose administrations (Day 1, visit 2-4) will be separated by at least five hours. The third dose, which is ZP4207(dasiglucagon) during hypoglycemia, will for all dosing visits be administered the next morning after a standardized carbohydrate-rich meal in the evening before. The patients will stay at the clinical site over night between Day 1 and Day 2. The dose of 0.6 mg will only be administered for ZP4207(dasiglucagon). The order of the micro-dose levels as well as the order of the treatment, ZP4207(dasiglucagon) vs. glucagon, will be randomized. For all patients the 0.6 mg dose of ZP4207(dasiglucagon) will be administered at visit 5.

For each dose level there will be 2 sets of PK/PD profiles for ZP4207(dasiglucagon), one initiated during euglycaemia and another during hypoglycaemia. Each patient enrolled will therefore provide a total of 11 PK/PD profiles covering four different dose levels; 8 profiles from ZP4207(dasiglucagon) and 3 profiles from glucagon

Inclusion Criteria:

To be included in the trial, patients have to fulfil all of the following criteria:

1. Signed and dated informed consent obtained before any trial-related activities. (Trial-related activities are any procedures that would not have been performed during normal management of the patient).
2. Male and female patients with T1DM for at least 1 year, as defined by the American Diabetes Association1.
3. Age between 18 and 64 years, both inclusive.
4. HbA1c < 8.5%.
5. C-peptide negative defined as below the lower limit of quantification.
6. Stable insulin regimen via an insulin infusion pump for at least 1 month prior to screening.
7. Weight between 60 kg and 90 kg, both inclusive.
8. Patients in good health according to age (medical history, physical examination, vital signs, 12-lead ECGs, lab assessments), as judged by the Investigator.-

Exclusion Criteria:

Patients meeting any of the following criteria during screening evaluations will be excluded from trial participation:

1. Unable to provide informed consent (e.g., impaired cognition or judgement).

2. Patients with mental incapacity or language barriers which preclude adequate understanding or cooperation, who are unwilling to participate in the trial, or who in the opinion of the Investigator should not participate in the trial.

3. Receipt of any medicinal product in clinical development within 3 months prior screening.

4. Previous exposure to ZP4207(dasiglucagon) or previously randomized to this trial.

5. Known or suspected allergy to trial product(s) or related products.

6. History of adverse reaction to glucagon (including allergy) besides nausea and vomiting.

7. History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction.

8. New onset clinically significant illness within 4 weeks prior to screening, as judged by the Investigator.

9. History of liver disease that is expected to interfere with the anti-hypoglycemia action of glucagon (e.g., liver failure or cirrhosis). Other liver disease (i.e., active hepatitis, steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen storage disease) may exclude the patient if it causes significant compromise to liver function or may do so in an unpredictable fashion.

10. Any history or presence of clinically relevant cardiovascular, pulmonary, respiratory, gastrointestinal, renal, metabolic, endocrinological (with the exception of conditions associated with diabetes mellitus), haematological, dermatological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, gynaecologic (if female), or infectious disease, or signs of acute illness as judged by the Investigator.

11. Clinically significant abnormal haematology, biochemistry or urinalysis screening tests, as judged by the Investigator. In particular, elevated liver enzymes (AST or ALT > 2 times the upper limit of normal, or bilirubin >1.5 the upper limit of normal) or impaired renal function (elevated serum creatinine values above the upper limit of normal).

12. Hypertension with systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg (excluding white-coat hypertension; therefore, if a repeated measurement shows values within the range, the patient can be included in the trial); a heart rate at rest outside the range of 50-90 beats per minute.

13. Clinically significant abnormal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position at screening, as judged by the Investigator.

14. Proliferative retinopathy or maculopathy and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator.

15. Inadequate venous access as determined by trial nurse or physician at time of screening

16. Any factors that, in the judgment of the Principal Investigator, would interfere with trial endpoints or the safe completion of the trial procedures.

17. Severe hypoglycaemic events within one year prior to screening, as judged by the Investigator.

18. Increased risk of thrombosis, e.g. patients with a history of deep leg vein thrombosis or family history of deep leg vein thrombosis, as judged by the Investigator.

19. Significant history of alcoholism or drug abuse as judged by the Investigator or consuming more than 24 g alcohol per day for men, or more than 12 g alcohol per day for women.

20. A positive result in the alcohol and/or urine drug screen at the screening visit.

21. Habitual smoking, i.e., daily smoking or more than 7 cigarettes/week within the last 3 months prior to screening. Patients have to accept refraining from smoking while at the clinical site.

22. History of cystic fibrosis, pancreatitis, pancreatic tumor, or any other pancreatic disease besides T1DM

23. History of pheochromocytoma.

24. History of adrenal disease or tumor.

25. Positive to the screening test for Hepatitis Bs antigen or Hepatitis C antibodies and/or a positive result to the test for HIV-1/2 antibodies or HIV-1 antigen.

26. The use of any non-prescribed systemic or topical medication, except routine vitamins and occasional use of acetylsalicylic acid and paracetamol within 2 weeks prior to randomization (and if female with the exception of hormonal contraception or menopausal hormone replacement therapy).

27. Donation of blood or plasma in the past month, or in excess of 500 mL within 12 weeks prior to screening.

28. Male who is sexually active and not surgically sterilized who or whose partner(s) is not using highly effective contraceptive methods (highly effective contraceptive measures include surgical sterilisation, hormonal intrauterine devices [coil], oral hormonal contraceptives, each in combination with spermicide-coated condoms), or who is not willing to refrain from sexual intercourse from the first dosing until the end of the trial (Visit 6).

29. Females of childbearing potential who are pregnant (positive urine human chorionic gonadotropin [HCG]), breast-feeding or intend to become pregnant or are not using highly effective contraceptive methods (highly effective contraceptive methods are considered those with a failure rate less than 1% undesired pregnancies per year including surgical sterilisation, hormonal intrauterine devices (coil), oral hormonal contraceptives, sexual abstinence or a surgically sterilised partner). Females who are postmenopausal can participate in the study without using adequate contraceptive methods. Postmenopausal is defined as women aged < 52 years and being amenorrheic for more than one year with serum FSH level > 40 IU/L or aged >= 52 years and being amenorrheic for less than one year and with serum FSH level > 40 IU/L or aged >= 52 years being amenorrheic for more than one year.

    -