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Liposomal Clodronate as a Novel Treatment for Imune-Mediated Hemolytic Anemia in Dogs (Study Closed)
January 30, 2008 (published)
Katharine Lunn
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Study Start Date: 01/01/2007
Study End Date: 12/31/2010

Liposomal Clodronate as a Novel Treatment for Immune-Mediated Hemolytic Anemia in Dogs

Immune-mediated hemolytic anemia (IMHA) is the most common cause of hemolytic anemia in dogs. Disease results from the extravascular removal of opsonized red blood cells (RBCs) by macrophages in the spleen and liver, or from intravascular RBC destruction. Reported mortality rates for IMHA are alarmingly high, ranging from 20% to 70%. Survival data for dogs with IMHA indicate that the most severely affected patients often die within 1 week of diagnosis, and patients surviving 10-14 days after initiation of treatment have improved survival times. Therefore there is a compelling need for safe, immediately effective immunosuppressive therapies for the management of IMHA. A treatment that could rapidly eliminate macrophages and block RBC destruction would allow time for conventional therapy with glucocorticoids and other immunosuppressive agents to take effect. Intravenous administration of liposome-encapsulated clodronate (LC) shows considerable promise in this area. This drug formulation has been shown to deplete macrophages in mice, and has been used as a novel agent for the treatment of IMHA in a mouse model. Recent studies have shown that LC induces killing of canine splenic macrophages and dendritic cells in vitro, and that infusion of LC inhibits clearance of opsonized RBCs in normal dogs. Most significantly, a preliminary study has shown that LC infusion is well tolerated in dogs, and survival rates were improved in a small group of patients with IMHA. This proposal describes a prospective randomized placebo-controlled clinical trial to assess the effects of LC on RBC indices and survival times in dogs with IMHA. When a case of IMHA is identified, and meets the inclusion criteria, liposomal clodronate or placebo will be shipped to the participating veterinarian, and samples will be sent back to CSU for analysis.

Results of a preliminary study can be downloaded from here.

Study Design:
Randomized, placebo-controlled, clinical trial

Sample Size:
48 dogs with IMHA

Complete study protocol can be downloaded from here.

Inclusion criteria:
Patient Selection Criteria:
Clinicopathological findings consistent with idiopathic IMHA:

  1. Regenerative anemia
  2. Presence of significant spherocytosis
  3. Positive Coombs, or in-saline autoagglutination, or flow cytometry positive for RBC-bound antibodies (this can be performed at CSU)

Initial Patient Evaluation:

  1. Complete blood count (CBC)
  2. Serum chemistry profile
  3. Urinalysis
  4. Thoracic radiographs
  5. Abdominal radiographs or ultrasound

Infectious disease testing - at clinician discretion. Patients will not be enrolled in the study until this initial testing is performed, to rule out concurrent illness. At the discretion of the attending clinician, patients may be enrolled if infectious disease test results are pending, provided the patient will receive "standard IMHA therapy", as outlined below.

Standard Therapy for IMHA
All patients enrolled in the study should receive the following therapy:

  1. Prednisone: 2 - 4 mg/kg/day initially (*for dogs that are vomiting, injectable dexamethasone may be used at a dose of 1/7-1/10 of the prednisone dose, once daily). Dose reductions at clinician discretion, according to control of the disease.
  2. Azathioprine: 1.5-2.5 mg/kg/day for 3 months. Dose adjustments may be made at clinician discretion, if adverse effects are noted. Patients that have initial severe adverse reactions to azathioprine will be removed from the study.
  3. Anticoagulation therapy at clinician's discretion.

Additional Acceptable Therapies (at clinician discretion):

  1. Supportive fluid therapy
  2. Transfusion of whole blood or packed RBCs
  3. Gastrointestinal protectants
  4. Antibiotics

Exclusion Criteria:

  1. Blood loss anemia.
  2. Non-immune-mediated hemolysis (for example microangiopathic hemolytic anemia, RBC parasites, toxins or hereditary RBC defects).
  3. Serious concurrent illnesses, including, but not limited to: neoplasia congestive heart failure, renal failure, pre-existing hepatic disease.
  4. Prior splenectomy.
  5. IMHA associated with an identified underlying disorder (for example neoplasia or a known drug reaction).
  6. Non-regenerative anemia due to immune-mediated bone marrow disease.
  7. Prior immunosuppressive or immunomodulatory therapy.
  8. Patients that cannot tolerate oral therapy.
  9. Patients already receiving therapy for IMHA will not be enrolled in the study. An exception can be made for patients that have received "standard therapy" for 24 hours or less, prior to enrollment (for example if a referring veterinarian gave a single dose of corticosteroid or azathioprine). Patients with concurrent immune-mediated thrombocytopenia may be enrolled, provided that they have concurrent IMHA, and not just blood loss anemia.

Excluded Medications: Patients may not receive the following treatments:

  1. Splenectomy
  2. Human immunoglobulin
  3. Equine immunoglobulin
  4. Hemoglobin-based oxygen carrying solutions such as Oxyglobin®
  5. Cyclophosphamide
  6. Cyclosporin
  7. Danazol
  8. Mycophenolate
Study Controls:
Placebo group

Study Endpoint(s):

  • Survival rates at 7 days, 14 days, and 3 months.
  • Duration of hospitalization
  • Costs of therapy
  • Requirement for blood transfusion
  • Surface-bound immunoglobulin on red blood cells
  • Resolution of spherocytosis and stabilization of PCV

EDTA blood (1 ml minimum) prior to liposome administration, and 1 week after liposomes. This is for flow cytometry. Samples must be shipped cold (not frozen) on ice-packs. A CBC is required daily after liposomes while the patient is hospitalized, and then at 7, 14, 21, and 28 days, and 3 months, after liposomes. These can be sent to CSU and performed at no charge. Or they can be performed by the primary care veterinarian, but must be sent to a diagnostic lab and include pathologist review of cell morphology. If CBCs are not performed at CSU, we require a slide of the blood smear, and a copy of the full CBC report. In addition, CSU will be shipping drug (or placebo) to the participating veterinarian.

$350 is available for each patient enrolled. This is divided into $250 given initially to offset the costs of the work-up of the patient and to cover shipping of samples. The remaining $100 is given when the 28 day sample has been received. Veterinarians must invoice the PI at CSU to receive the reimbursements. We cannot send a check directly to the clients.

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Full Disclosure information:

  • The study is funded by a grant from the Morris Animal Foundation.
  • The investigators do not have any conflict of interest.
  • The study will be published if results are negative.
  • The study will be reported on VIN.
  • The authors will acknowledge VIN if the study is published.

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