Randomized Trial of IVIg With or Without Cyclophosphamide in Pemphigus
Study Details
Study Description
Brief Summary
The purpose of this study is to compare two standard treatments for pemphigus to determine which more effectively improves the clinical manifestations of the disease and decreases serum level of the autoantibodies which cause the disease.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Group A IVIg alone (intravenous immunoglobulin) |
Drug: intravenous immunoglobulin
Gamunex 10% 500/mg/kg/day x four days per cycle total of four cycles
Other Names:
|
| Experimental: Group B IVIg with cyclophosphamide |
Drug: intravenous immunoglobulin
Gamunex 10% 500/mg/kg/day x four days per cycle total of four cycles
Other Names:
Drug: cyclophosphamide
cyclophosphamide dose of 2mg/kg/day divided into three-times daily oral administration
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Clinical Outcome: Extent and Severity of Disease [6 - 10 weeks after initiation of therapy]
- Serum Levels of Pemphigus Antibodies [6-10 weeks after initiation of therapy]
Secondary Outcome Measures
- Toxicity of Treatment: Measured in Renal Toxicity, Myelosuppression or Hepatic Toxicity [Throughout course of study]
- Ability to be Weaned Off Steroids [Measured 6 and 10 weeks after initiation of IVIg treatment]
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | NYU Medical Center | New York | New York | United States | 10016 |
Sponsors and Collaborators
- NYU Langone Health
Investigators
- Principal Investigator: Jean-Claude Bystryn, M.D., NYU MEDICAL CENTER
Study Documents (Full-Text)
None provided.More Information
Publications
- Czernik A, Beutner EH, Bystryn JC. Intravenous immunoglobulin selectively decreases circulating autoantibodies in pemphigus. J Am Acad Dermatol. 2008 May;58(5):796-801. doi: 10.1016/j.jaad.2008.01.007.
- Czernik A, Bystryn JC. Improvement of intravenous immunoglobulin therapy for bullous pemphigoid by adding immunosuppressive agents: marked improvement in depletion of circulating autoantibodies. Arch Dermatol. 2008 May;144(5):658-61. doi: 10.1001/archderm.144.5.658.
- Czernik A, Bystryn JC. Kinetics of response to conventional treatment in patients with pemphigus vulgaris. Arch Dermatol. 2008 May;144(5):682-3. doi: 10.1001/archderm.144.5.682.
- Green MG, Bystryn JC. Effect of intravenous immunoglobulin therapy on serum levels of IgG1 and IgG4 antidesmoglein 1 and antidesmoglein 3 antibodies in pemphigus vulgaris. Arch Dermatol. 2008 Dec;144(12):1621-4. doi: 10.1001/archdermatol.2008.503.
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Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | IVIg Alone | IVIg With Cyclophosphamide |
|---|---|---|
| Arm/Group Description | IVIg alone intravenous immunoglobulin: Gamunex 10% 500/mg/kg/day x four days per cycle total of four cycles | IVIg with cyclophosphamide cyclophosphamide: cyclophosphamide dose of 2mg/kg/day divided into three-times daily oral administration |
| Period Title: Overall Study | ||
| STARTED | 5 | 4 |
| COMPLETED | 4 | 3 |
| NOT COMPLETED | 1 | 1 |
Baseline Characteristics
| Arm/Group Title | Group A | Group B | Total |
|---|---|---|---|
| Arm/Group Description | IVIg alone intravenous immunoglobulin: Gamunex 10% 500/mg/kg/day x four days per cycle total of four cycles | IVIg with cyclophosphamide cyclophosphamide: cyclophosphamide dose of 2mg/kg/day divided into three-times daily oral administration | Total of all reporting groups |
| Overall Participants | 5 | 4 | 9 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
1
20%
|
1
25%
|
2
22.2%
|
| >=65 years |
4
80%
|
3
75%
|
7
77.8%
|
| Age (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
61.2
|
56.25
|
59
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
2
40%
|
3
75%
|
5
55.6%
|
| Male |
3
60%
|
1
25%
|
4
44.4%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
5
100%
|
4
100%
|
9
100%
|
Outcome Measures
| Title | Clinical Outcome: Extent and Severity of Disease |
|---|---|
| Description | |
| Time Frame | 6 - 10 weeks after initiation of therapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| Sadly, the trial PI, Dr. Jean-Claude Bystryn, died on August 19, 2010. As a result the study could not be completed and an analysis of the data collected was not performed. |
| Arm/Group Title | IVIg Alone | IVIg With Cyclophosphamide |
|---|---|---|
| Arm/Group Description | IVIg alone intravenous immunoglobulin: Gamunex 10% 500/mg/kg/day x four days per cycle total of four cycles | IVIg with cyclophosphamide cyclophosphamide: cyclophosphamide dose of 2mg/kg/day divided into three-times daily oral administration |
| Measure Participants | 0 | 0 |
| Title | Serum Levels of Pemphigus Antibodies |
|---|---|
| Description | |
| Time Frame | 6-10 weeks after initiation of therapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| Sadly, the trial PI, Dr. Jean-Claude Bystryn, died on August 19, 2010. As a result the study could not be completed and an analysis of the data collected was not performed. |
| Arm/Group Title | IVIg Alone | IVIg With Cyclophosphamide |
|---|---|---|
| Arm/Group Description | IVIg alone intravenous immunoglobulin: Gamunex 10% 500/mg/kg/day x four days per cycle total of four cycles | IVIg with cyclophosphamide cyclophosphamide: cyclophosphamide dose of 2mg/kg/day divided into three-times daily oral administration |
| Measure Participants | 0 | 0 |
| Title | Toxicity of Treatment: Measured in Renal Toxicity, Myelosuppression or Hepatic Toxicity |
|---|---|
| Description | |
| Time Frame | Throughout course of study |
Outcome Measure Data
| Analysis Population Description |
|---|
| Sadly, the trial PI, Dr. Jean-Claude Bystryn, died on August 19, 2010. As a result the study could not be completed and an analysis of the data collected was not performed. |
| Arm/Group Title | IVIg Alone | IVIg With Cyclophosphamide |
|---|---|---|
| Arm/Group Description | IVIg alone intravenous immunoglobulin: Gamunex 10% 500/mg/kg/day x four days per cycle total of four cycles | IVIg with cyclophosphamide cyclophosphamide: cyclophosphamide dose of 2mg/kg/day divided into three-times daily oral administration |
| Measure Participants | 0 | 0 |
| Title | Ability to be Weaned Off Steroids |
|---|---|
| Description | |
| Time Frame | Measured 6 and 10 weeks after initiation of IVIg treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| Sadly, the trial PI, Dr. Jean-Claude Bystryn, died on August 19, 2010. As a result the study could not be completed and an analysis of the data collected was not performed. |
| Arm/Group Title | IVIg Alone | IVIg With Cyclophosphamide |
|---|---|---|
| Arm/Group Description | IVIg alone intravenous immunoglobulin: Gamunex 10% 500/mg/kg/day x four days per cycle total of four cycles | IVIg with cyclophosphamide cyclophosphamide: cyclophosphamide dose of 2mg/kg/day divided into three-times daily oral administration |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | 3 years | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Group A | Group B | ||
| Arm/Group Description | IVIg alone intravenous immunoglobulin: Gamunex 10% 500/mg/kg/day x four days per cycle total of four cycles | IVIg with cyclophosphamide cyclophosphamide: cyclophosphamide dose of 2mg/kg/day divided into three-times daily oral administration | ||
All Cause Mortality |
||||
| Group A | Group B | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Group A | Group B | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/5 (20%) | 1/4 (25%) | ||
| Cardiac disorders | ||||
| Atrial Fibrillation not considered related to treatment | 0/5 (0%) | 0 | 1/4 (25%) | 1 |
| Elevated blood pressure; blurred vision, nausea and tearing | 1/5 (20%) | 1 | 0/4 (0%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Group A | Group B | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/5 (100%) | 4/4 (100%) | ||
| Blood and lymphatic system disorders | ||||
| Anemia | 2/5 (40%) | 2 | 1/4 (25%) | 1 |
| leukopenia | 0/5 (0%) | 0 | 1/4 (25%) | 1 |
| Cardiac disorders | ||||
| Chest Tightness | 1/5 (20%) | 1 | 0/4 (0%) | 0 |
| Hypertension | 4/5 (80%) | 4 | 0/4 (0%) | 0 |
| Angina | 1/5 (20%) | 1 | 0/4 (0%) | 0 |
| Gastrointestinal disorders | ||||
| Mild Nausea | 1/5 (20%) | 1 | 0/4 (0%) | 0 |
| Infections and infestations | ||||
| Oral Candida Infection | 0/5 (0%) | 0 | 1/4 (25%) | 1 |
| Nail infection | 0/5 (0%) | 0 | 1/4 (25%) | 1 |
| Injury, poisoning and procedural complications | ||||
| Food Poisoning | 1/5 (20%) | 1 | 0/4 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Mild Muscle Pain | 1/5 (20%) | 1 | 1/4 (25%) | 1 |
| Nervous system disorders | ||||
| Headache | 1/5 (20%) | 1 | 1/4 (25%) | 1 |
| Vasovega | 1/5 (20%) | 1 | 0/4 (0%) | 0 |
| Renal and urinary disorders | ||||
| Increased Creatine Levels | 1/5 (20%) | 1 | 0/4 (0%) | 0 |
| Elevated Urine Protein Levels | 2/5 (40%) | 2 | 0/4 (0%) | 0 |
| Urinary Tract Infection | 1/5 (20%) | 1 | 1/4 (25%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Pulmanary Adema | 0/5 (0%) | 0 | 1/4 (25%) | 1 |
| Skin and subcutaneous tissue disorders | ||||
| Localized minor inflammation | 1/5 (20%) | 1 | 0/4 (0%) | 0 |
| Mild skin infection | 1/5 (20%) | 1 | 0/4 (0%) | 0 |
| Penile Ulcer | 1/5 (20%) | 1 | 0/4 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Elise Kelman, Associate Director of Research Administration |
|---|---|
| Organization | NYU School of Medicine |
| Phone | 2122639073 |
| elise.kelman@nyumc.org |
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