Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases

A Phase III, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics and Safety of Subgam-VF in Primary Immunodeficiency Diseases

The main objective of the study is to determine the pharmacokinetics profile of Subgam-VF. The secondary objectives are to assess the safety of Subgam-VF and refine the dose adjustment coefficient for Subgam-VF needed for subjects switching from prior intravenous immunoglobulin (IGIV) therapy.

This will be a Phase III, multicenter, open-label, non-randomized study.

Following a screening period, eligible subjects will commence weekly Subgam-VF treatment; this is a 16% subcutaneous IgG product.

Subjects will receive Subgam-VF for 26 weeks during which time safety will be assessed.

After Week 21, PK sampling will commence.

Follow-up visit (one week after the last Subgam-VF infusion, Week 27). All AEs will be monitored up to 28 days after the last Subgam-VF infusion by telephone contact (Week 30).

Subgam-VF will be administered subcutaneously using infusion pumps.

Subjects will be given diaries to record adverse event data as well as any infusions administered at home. In addition there will be a telephone follow up by an appropriately qualified site staff member on day 3 after each site administered and home administered infusion to check for any adverse reactions including infusion site reactions and remind subjects to document these in their subject study diary.

Inclusion criteria:

1. Aged between 2 and 75 years (at time of initial consent).

2. Body Mass Index (BMI) < 46 for adults (aged 16 years & older), & BMI < 28 for children.

3. Diagnosed with primary immunodeficiency disease e.g. common variable immunodeficiency, X-linked & autosomal forms of agammaglobulinaemia, hyper-IgM syndrome, Wiskott-Aldrich syndrome.

4. Currently receiving a licensed (or investigational stage III, IIIb) IGIV or SCIG and

   1. IGIV dose is between 300 and 800 mg/kg/month. SCIG dose is between 110 & 300 mg/kg/week;
   2. Dose is stable for at least the past three months (i.e. consistent mg/kg +/- 5%);
   3. The infusion interval is every 21 or 28 days for IGIV & seven days for SCIG;
   4. Has a documented trough level of ≥ 6 g/L (600 mg/dL) on current IgG therapy. If not available can be obtained at the screening visit, Visit 1 (Week 0).

5. Female subjects who are (or become) sexually active must practice contraception by using a method of proven reliability for the duration of the study.

6. Females of child-bearing potential, (defined from the onset of menstruation to one year post menopause), must have a negative result on a urine HCG-based pregnancy test.

7. Willing to comply with all aspects of the protocol, including blood sampling, for the duration of the study.

8. Signed an informed consent form. In the case of subjects under the legal age the parent/guardian will sign an informed consent form & where appropriate the subject will sign an assent form.

Exclusion Criteria:

1. Has a history of any severe anaphylactic reaction to blood or any blood-derived product.

2. Has selective IgA deficiency or has a history of antibodies to IgA.

3. Has clinically significant impairment of cellular or innate immunity at the discretion of the Investigator

4. Has evidence of an active infection at the time of enrolment (i.e. on day of first infusion). Subjects who are asymptomatic but have not completed their course of antibiotics are eligible.

5. Has previously completed or withdrawn from this study.

6. Is currently receiving, or has received, any investigational agent within the prior three months, unless it is an investigational stage III, IIIb IGIV or SCIG.

7. Is pregnant (confirmed by a positive result on an HCG-based pregnancy test) or is nursing.

8. Is positive for any of the following at screening:

   • Serological test for HIV 1&2, HCV, or HBsAg

9. Has levels at screening greater than 2.5 times the upper limit of normal as defined at the central laboratory of any of the following:

   • Alanine transaminase (ALT)
   • Aspartate transaminase (AST)

10. Has severe renal impairment (defined as serum creatinine greater than two times the upper limit of normal or BUN greater than two times the upper limit of normal for the range of the laboratory doing the analysis); the subject is on dialysis; or has a history of acute renal failure.

11. Is known to abuse alcohol, opiates, psychotropic agents, or other chemicals or drugs, or has done so within the past 12 months.

12. Has a history of DVT, or thrombotic complications of IgG therapy, or a prior diagnosis of thrombophilia.

13. Suffers from any acute or chronic medical condition, (e.g. renal disease or predisposing conditions for renal disease, coronary artery disease, or protein losing state, proteinuria) that the Investigator feels may interfere with the conduct of the study.

14. Has an acquired medical condition, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or recurrent neutropenia (ANC < 1 x 109/L).

15. Is receiving the following medication:

    • Steroids (long-term daily, > 0.15 mg of prednisone equivalent/kg/day). Requirement for short or intermittent courses of > 0.15mg/kg/day would not exclude a subject.
    • Immunosuppressive drugs
    • Immunomodulatory drugs

16. If ≥ 18 years of age, has non-controlled arterial hypertension (systolic blood pressure > 160 mmHg &/or diastolic blood pressure > 100 mmHg). For younger subjects refer to current guidelines for diagnosis of blood pressure1.

17. Has anemia (hemoglobin < 10 g/dL) at screening.

18. Has severe dermatitis that would preclude sites for safe product administration.