Multicenter, open-label extension study to investigate the long-term safety and efficacy of IgPro20 in maintenance treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in subjects completing study IgPro20_3003.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired
neurological, demyelinating neuropathy with an assumed autoimmune-mediated
pathogenesis. The clinical course can be relapsing/remitting or chronic and
progressive, the former being much more common in young adults.

The prevalence of CIDP is estimated to be about 4.7 per 100,000 adults and
about 0.5 per 100,000 children.

Primary treatment modalities include IVIGs (normal human immunoglobulin for
intravenous administration) and plasma exchange and corticosteroids, with the
choice usually based on availability, cost, and side-effect profile.

IgPro20 is a ready-to-use formulation of human immunoglobulin G (IgG) with *98%
purity for subcutaneous (SC) administration. It is approved in the United
States of America (US), the European Union, Switzerland, Latin America, eastern
Europe, Canada, Japan, and Australia under the brand name Hizentra® for primary
immunodeficiency syndromes, and is manufactured at CSL Behring*s (CSLB*s)
facility in Berne, Switzerland.

The current study is an extension study to the pivotal study IgPro20_3003.
Clinical studies have demonstrated the clinical efficacy and safety of using
IVIGs to treat CIDP. Study IgPro20_3003 is being conducted to provide evidence
of subcutaneous immunoglobulin (SCIG) as an alternative treatment option for
CIDP in demonstrating safety and efficacy of IgPro20 as maintenance therapy in
subjects treated with IVIG and switched to SCIG.
The current extension study will provide further insight into the long-term
safety and efficacy of treatment with IgPro20.

Primary objective: To evaluate the long-term safety of IgPro20.

Secondary objectives:
* To evaluate the long-term safety of IgPro20 by dose.
* To evaluate the efficacy of IgPro20.

Exploratory objectives:
* To evaluate health-related quality of life (HRQL).
To evaluate serum immunoglobulin G (IgG) levels.

This is an open-label prospective, multicenter extension study for subjects who
have completed subcutaneous (SC) Week 25 or were successfully rescued from a
CIDP relapse during the SC Treatment Period of the preceding pivotal study
IgPro20_3003. All eligible subjects must transition directly from study
IgPro20_3003 to the extension study IgPro20_3004.
Eligible subjects will receive open-label IgPro20 (0.2 g/kg body weight [bw])
weekly for 48 weeks.
Subjects who relapse on IgPro20 0.2 g/kg bw will be given the option to remain
in the study with an increase in the IgPro20 dose to 0.4 g/kg bw. Subjects
remaining in the study on IgPro20 0.4 g/kg bw will have to successfully recover
from the CIDP relapse within 4 weeks (±2 days), as confirmed by a site visit,
or will otherwise be withdrawn from the study.
Successful recovery after a CIDP relapse is defined as the return of the total
adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) score back to (or
better than) the baseline score.
The last dose of IgPro20 is administered at Week 48; after the completion visit
(Week 49) the subject is treated at the discretion of the investigator with
standard of care therapy, ie, the subject will return to the CIDP treatment
prescribed by the treating physician. If a subject has a CIDP relapse with less
than 4 weeks remaining before the completion visit (Week 49), the subject will
continue on the study and have the completion visit (Week 49) as planned
followed by treatment at the discretion of the investigator with standard of
care therapy.
A subject enrolled under the original protocol (09 Dec 2013) will convert to
Amendment 2 procedures at Week 25 after Amendment 2 approval at the site
(conversion to Amendment 2 may be later than Week 25 if the site has not yet
been granted approval). An IgPro20 dose adjustment from 0.4 to 0.2 g/kg bw will
be required for subjects who did not experience a CIDP relapse during the first
25 weeks. For subjects under the original protocol (09 Dec 2013) who recovered
from a CIDP relapse during the first 25 weeks, their IgPro20 dose will be
maintained at 0.4 g/kg bw for the remainder of the study. If they experience a
second relapse after Week 25, they will be withdrawn from the study, as per
this amendment.

The study duration will be up to 49 weeks. The last dose of IgPro20 is
administered at Week 48.
* 48 weeks of low dose IgPro20.
If CIDP relapse occurs, high dose IgPro20 until Week 48.

RISK-BENEFIT ASSESSMENT

Risk
In the 3 pivotal studies performed by CSLB for approval of IgPro20 in primary
immunodeficiency syndromes, almost all adverse events (AEs [99%]) were mild or
moderate in intensity. There was no dose-dependent increase in the overall rate
of AEs, and there was no evidence in either study of severe systemic AEs.
The most frequently reported AEs in these studies were local reactions
(swelling, erythema, warmth, bruising, pain, pruritis), followed by headache,
diarrhea, fatigue, back pain, nausea, arthralgia, pain in extremity, cough,
rash, pruritis, vomiting, upper abdominal pain, migraine, fever and pain. In
addition, in the postmarketing setting, reactions such as hypersensitivity,
tremor, burning sensation and infusion site ulcer were reported; as well as
rare events such as anaphylaxis, aseptic meningitis syndrome (AMS) and
thrombotic events. SC infusions generally result in lower rates of headache and
other systemic adverse reactions than IV infusions, which is attributed to the
more stable serum IgG concentrations attained with SCIG treatment (see Hizentra
Investigator*s Brochure). Clinical trial and postmarketing experience with
IgPro20 in pediatric and geriatric patients shows an overall similar safety
profile as in adult patients.
The risk that products manufactured from plasma could transmit an infectious
agent has been reduced by screening plasma donors for prior exposure to
pathogens and by testing the donations for the presence of certain markers of
infections. In addition, different complementary virus elimination processes
used during the manufacture of IgPro20 (incubation at pH 4, virus filtration,
fractionation, and depth filtration) effectively reduce the potential for viral
transmission. The manufacturing process was also investigated for its capacity
to eliminate hamster-adapted scrapie agent 263K, which is considered to be a
model for Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease. The
results demonstrated substantial removal of the infectious agent by the
manufacturing process in all model systems. To date, no viral infection related
to the infusion of IgPro20 was reported. However, the possibility of
transmitting infective agents cannot be totally excluded.
At the start of this extension study, the pivotal study is still ongoing.
Therefore, no final assessment of the efficacy and safety of IgPro20 in CIDP
will have been performed. Depending on these results, the extension study may
be modified, terminated, or continued as planned.

Justification for IgPro 20 Dose used in this extension study
The preplanned IgPro20_3003 safety interim analysis (March 2014) after 89
subjects were randomized to IgPro20 or placebo treatment revealed no safety
issue. Altogether, a total of 2463 infusions were administered for the 3
treatment arms (IgPro20 0.4 g/kg bw; IgPro20 0.2 g/kg bw; and placebo). There
were 4 (4.5%) subjects with serious treatment-emergent adverse events (2
subjects with arthralgias, 1 subject with acute allergic skin reaction, and 1
subject who required surgery of his ankle). In only 1 subject was the serious
treatment-emergent adverse event (acute allergic skin reaction) assessed as
related to the blinded study drug. All these events were of temporary duration
and the subjects recovered completely by the end of the study. These results
suggest that both doses of IgPro20 were well tolerated.
The low IgPro20 dose from Study IgPro20_3003 has been chosen for this study as
it is suggested to be the minimum effective dose necessary to maintain CIDP.
High IgPro20 dose subjects in Study IgPro20_3003 will have their dose reduced *
which is in line with current guidelines to lower the dose after a period of
stability. Low dose subjects in Study 3003 will continue with their low dose,
and placebo subjects in Study 3003 will start with the low dose.
The low IgPro20 dose will be administered in a lower volume, unlike in Study
3003 where half of the low IgPro20 dose consisted of placebo in order to allow
for blinding of the higher volume necessary for high IgPro20 dose treatment. It
is therefore assumed that the low IgPro20 dose will be at least as safe in
subjects participating in the extension study (minimizing local site reactions
due to lower volume) while still being effective to control the CIDP.
In conclusion, the lowIgPro20 dose from Study 3003 has been chosen for this
extension study as the probable minimum effective dose. The dose change does
not pose a specific risk and is recommended by current treatment guidelines.
Also see Section 9.1.3 *Adverse Events of Special Interest*.

Benefit
The expected benefit of the extension study for subjects is the continuation of
SCIG therapy in subjects a) who have completed the pivotal study and were
treated with either high dose or low dose IgPro20; or b) who have relapsed in
the pivotal study on placebo
Volume up to 50 mL per infusion site
In Study 3003 up to 40 mL per infusion site is allowed. The preplanned safety
interim analysis (March 2014) after 89 patients were randomized to
IgPro20/placebo treatment revealed no safety issues with regards to infusion
volume. The maximum infusion volume per site has therefore been increased to 50
mL in this study. This allows a syringe (50 mL) of IgPro20 to be used without
changing infusion needles which is expected to increase comfort, decrease pain
and decrease infusion time. The infusion method details are described in
Section 6.4.1.