Randomized Trial of IVIg With or Without Cyclophosphamide in Pemphigus

Pemphigus is a serious and life-threatening autoimmune disease characterized by blisters and
erosions that occur on the skin and oral mucosa. It is caused by autoantibodies that attack
desmoglein 1 and 3, adhesion molecules that are present on the surface of the cells
(keratinocytes) that make up the superficial layer of the skin. As a result these cells stop
sticking together, and come apart resulting in the formation of blisters on the skin.

Pemphigus is usually treated with systemic corticosteroids often given together with
immunosuppressive drugs such as Cytoxan (cyclophosphamide), Imuran (azathioprine),
methotrexate, CellCept (mycophenolate mofetil) and others. However, the prolonged and high
doses of systemic steroids and other immunosuppressive agents used to treat the disease are
associated with significant toxicity.

A new treatment which is now being used to treat pemphigus patients that are unresponsive,
or that have developed complications to conventional treatment is IVIg (intravenous
immunoglobulin). IVIg consists of one of the protein fractions present in blood. It is the
fraction that contains antibodies and is called immunoglobulin (Ig). It is purified from
blood that has been collected from thousands of donors and treated to remove potential
infectious agents. It is administered intravenously (IV) over several hours, several days in
succession. The cycles are usually repeated every 2 to 4 weeks until the disease is
controlled.

IVIg treatment is currently given in either of two ways, either by itself or with an
immunosuppressive drug such as cyclophosphamide or azathioprine. It is unknown which of
these two procedures is better. This trial is being conducted to determine which treatment
is more effective.

The trial is being conducted in patients with pemphigus that are not responding to, or have
developed complications from, standard treatment. All patients will be treated with IVIg
administered using a standard protocol. The IVIg will be given daily for 4 days, and this
cycle will be repeated every other week for a total of 4 cycles. In addition, half of the
patients will be selected by chance to also be treated with cyclophosphamide, an
immunosuppressive drug often used to treat other autoimmune diseases including pemphigus.
The cyclophosphamide is a pill that is taken 3 times a day. A total of 12 patients will be
treated in each arm of the trial. The trial is being conducted by Dr. Jean-Claude Bystryn at
the New York University Medical Center.

The extent and activity of the disease, as well as the blood levels of pemphigus antibodies,
will be measured at baseline prior to entry into the trial and periodically during the
trial.

The goal of the study is to determine whether there is a difference between the two
treatments in the rate at which: 1) the activity and extent of the disease improves, 2) the
dose of corticosteroids required to treat the disease can be reduced, and 3) the blood level
of pemphigus antibodies decrease.

This trial will test this hypothesis by examining whether IVIg treatment given with
cyclophosphamide results in a more rapid decline in circulating pemphigus antibodies than
when given alone.

Inclusion Criteria:

- Lesions consistent with pemphigus foliaceus or vulgaris

- Diagnosis confirmed by histology and IIF ≥ 40 within past month

- On ≥20mg/day of prednisone per day for two weeks or ≥ 80mg/day for one week

- Women of childbearing potential negative HCG obtained two weeks prior to first IVIg

- Agrees to two acceptable forms of contraception* if randomized to cyclophosphamide
group:

- IUD (except progesterone T), Combination oral contraceptives, transdermal patch,
vaginal ring, hormonal injectables or implantables, male latex condom, diaphragm,
cervical cap, or vaginal sponge (contains spermicide)

- Normal organ function confirmed by CBC, UA, LFTs and Ig levels within defined
inclusion criteria

- Responds yes to at least one of the criteria below:

- Persistence of clinical manifestations of disease despite steroid treatment

- Flare in disease activity after an attempt at steroid tapering

- Failure of established lesions to heal

- Rapidly progressive disease.

- Conventional therapy is relatively contraindicated i.e. side effects, co-morbid
conditions

- systemic infections, peptic ulcers, osteoporosis, hypertension, cataracts or others

Exclusion Criteria:

- Use of IVIg within past 3 weeks or the use of a cytotoxic drug within the past 2
weeks

- Participating in another clinical trial at the time of screening and enrollment

- Medical condition that precludes use of IVIg or cyclophosphamide (i.e. pregnancy
breastfeeding, underlying chronic infection, concurrent opportunistic infection,
sepsis or volume depletion

- Renal insufficiency ( GFR <90, proteinuria (>1+, x 2), creatinine >1.8 or increased
WBC or RBCs which cannot be explained by cystitis.)

- Known hypersensitivity to study drugs, IVIg or cyclophosphamide