Study of Cyclosporine or Corticosteroids as an Adjunct to Plasma Exchange in Thrombotic Thrombocytopenic Purpura (TTP)

A Multi-Center, Randomized Study of Cyclosporine or Corticosteroids as an Adjunct to Plasma Exchange in the Initial Therapy of Thrombotic Thrombocytopenic Purpura (TTP)

This research involves the use of immune base therapy as an adjunct to plasma exchange, the present standard of care for thrombotic thrombocytopenic purpura (TTP). Funding source -FDA OOPD

Study Overview

• Status: Completed
• Conditions: Thrombotic Thrombocytopenic Purpura
• Intervention / Treatment: Drug: Cyclosporine; Drug: Prednisone

Detailed Description

TTP is a rare blood disorder that causes blood clots to form in the small blood vessels throughout the body, including the kidneys, brain, abdomen, and the heart. Plasma exchange is the standard treatment for TTP. Plasma exchange is a treatment that removes the plasma (the liquid portion of the blood without any cells) from a patient and replaces it with plasma from a donor. With plasma exchange, 90% of patients achieve a remission of the disease. Unfortunately, up to one half of patient will relapse after the plasma exchange has stopped, leading to significant complications and added risks to the patient.

This study randomizes patients to receive either prednisone or cyclosporine as an adjunct to plasma exchange, with the cyclosporine arm being the experimental arm of the study. All patients will undergo plasma exchange but will be randomized to receive either prednisone or cyclosporine as an adjunct to plasma exchange. Previous studies suggested that cyclosporine was superior to prednisone as an adjunct to plasma exchange, and therefore this randomized study attempts to confirm the findings of two previous single institution studies.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with a clinical diagnosis of idiopathic TTP as defined by a microangiopathic hemolytic anemia and thrombocytopenia (<100 x 103)
• Additional components of the pentad (fever, renal and neurologic abnormalities) need not be present.
• Additional explanations for the microangiopathic changes including DIC and malignancy should be excluded.
• Patients with pregnancy associated TTP will be permitted on this therapeutic trial if the child is delivered prior to the initiation of therapy for TTP. However, female patients that are breastfeeding and are unwilling to discontinue breastfeeding at the time of enrollment will be excluded from this study
• Patients with a previous diagnosis of TTP are eligible to be enrolled provided they meet eligibility criteria and have not been treated for an TTP in the past 30 days
• Given the potential for nephrotoxicity with CSA, all patients must have a serum creatinine of < 2.5 mg/dl prior to enrollment

Exclusion Criteria:

• In light of concern for the prompt initiation of PE, all patients with suspected TTP may be enrolled on this trial. If it is subsequently found that the patient does not meet enrollment criteria, they will be removed and their spot replaced for study purposes. Patients removed from the study after enrollment will continue to be followed longitudinally for 6 months to be monitored for safety and will be included in the safety database.
• Patients with TTP clinically categorized as secondary to stem cell transplant and solid organ, bloody diarrhea associated, malignancy associated, and drug associated will not be enrolled on this therapeutic study.
• Incarcerated patients will be excluded from the study due to the inherent difficulties in maintaining close follow-up for study purposes in patients who are incarcerated.
• Any patients already being treated chronically with corticosteroids or cyclosporine and taking these at the time of their presentation will be excluded from this study.
• Female patients that are breastfeeding and are unwilling to discontinue breastfeeding at the time of enrollment will be excluded from this study
• Patients taking any medications contraindicated in combination with CSA that cannot be safely discontinued will be excluded from this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cyclosporine and Plasma Exchange Arm; Patients in this arm will receive cyclosporine (Neoral) at a dose of 2-3 mg/kg orally as an adjunct to plasma exchange. All patients initiated daily PEX (one plasma volume), using plasma as the replacement fluid. Patients randomized to the CSA arm received CSA at a dose of 2-3 mg/kg (rounded to the nearest 50 mg increment) divided into a twice daily dosing (Figure 1a). Patients randomized to CSA did not receive steroids, but were permitted to receive hydrocortisone as required for any hypersensitivity reactions to the infused plasma. Daily PEX was continued until a clinical response was achieved, then patients received PEX every other day for 2 additional procedures, with the first day that the platelet count and LDH were normal counting as the first of the 2 procedures.	Drug: Cyclosporine; 2-3 mg/kg orally in a twice day divided dose for 6 months; Other Names: Neoral
Active Comparator: Prednisone and Plasma Exchange Arm; Patients in this arm will receive prednisone at a dose of 1 mg/kg as an adjunct to plasma exchange. All patients initiated daily PEX (one plasma volume), using plasma as the replacement fluid. Patients randomized to the corticosteroid arm received prednisone at a dose of 1 mg/kg/d rounded to the nearest 20 mg increment. Daily PEX was continued until a clinical response was achieved, then patients received PEX every other day for 2 additional procedures, with the first day that the platelet count and LDH were normal counting as the first of the 2 procedures.	Drug: Prednisone; 1 mg/kg orally, daily for at least 30 days, then tapered over 30 days after achieving remission.; Other Names: Steroid arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Exacerbations in the CSA/PEX Arm Compared to the Steroids/PEX Arm	Number of Participants with Exacerbations in the CSA/PEX Arm Compared to the Steroids/PEX Arm	From the start of treatment until 30 days after discharge from the last PEX procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time in Days to Achieve a Clinical Response, Comparing the CSA/PEX Arm to the Steroids/PEX Arm.	Days to achieve a clinical response, defined as a normal platelet count (>150 x 109/L), normal LDH, and no new end organ injury.	Time to starting treatment until 6 months after the last PEX procedure

Collaborators and Investigators

• Sponsor: Ohio State University
• Collaborators: Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Spero R Cataland, MD, Ohio State University

Publications and helpful links

General Publications

• Cataland SR, Kourlas PJ, Yang S, Geyer S, Witkoff L, Wu H, Masias C, George JN, Wu HM. Cyclosporine or steroids as an adjunct to plasma exchange in the treatment of immune-mediated thrombotic thrombocytopenic purpura. Blood Adv. 2017 Oct 23;1(23):2075-2082. doi: 10.1182/bloodadvances.2017009308. eCollection 2017 Oct 24.

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): September 20, 2017
• Study Completion (Actual): September 20, 2017

Study Registration Dates

• First Submitted: July 9, 2008
• First Submitted That Met QC Criteria: July 9, 2008
• First Posted (Estimate): July 11, 2008

Study Record Updates

• Last Update Posted (Actual): May 3, 2023
• Last Update Submitted That Met QC Criteria: April 29, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Treatment; Exacerbation; Relapse; Plasma Exchange; Idiopathic TTP
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Hematologic Diseases; Hemorrhage; Blood Coagulation Disorders; Skin Manifestations; Thrombocytopenia; Blood Platelet Disorders; Thrombophilia; Thrombotic Microangiopathies; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Prednisone; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 2007H0194; R01FD003932 (U.S. FDA Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: data being evaluated and reviewed, manuscript in preparation for final report to FDA
• IPD Sharing Time Frame: Presently available to share
• IPD Sharing Access Criteria: Request needs to be made to investigators
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR