Low Dose Rituximab in Thrombotic Thrombocytopenic Purpura

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01554514
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 19
• Locations: 4
• Arm: 1
• Duration (Months): 90.4
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by small blood clots throughout the body that can damage major organs and cause death. TTP is treated with plasma exchange (also called "plasmapheresis"). Patients who do not respond initially to plasma exchange often are helped by later treatment with rituximab. The purpose of this study is to see whether combining low doses of rituximab with plasma exchange will help patients get better sooner and reduce the chance of getting TTP again.

Condition or Disease	Intervention/Treatment	Phase
Thrombotic Thrombocytopenic Purpura	Biological: rituximab	Phase 2

Detailed Description

This is a pilot safety/efficacy study of adjuvant low dose rituximab (100 mg/week x 4 doses) plus standard plasma exchange and corticosteroids for the treatment of thrombotic thrombocytopenic purpura (TTP) with severe ADAMTS13 deficiency. Results for study subjects will be compared to historical controls treated initially with plasma exchange and corticosteroids. This study proposes to test the hypothesis that adjuvant low dose rituximab may decrease the incidence of a composite primary endpoint (exacerbations or refractory disease) in acquired TTP with severe ADAMTS13 deficiency. A novel ADAMTS13 assay will be used to identify patients with TTP and severe ADAMTS13 deficiency for enrollment, and to assess the utility of ADAMST13 as a biomarker for response to therapy and prognosis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Adjuvant Low Dose Rituximab for Acquired TTP With Severe ADAMTS13 Deficiency
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Feb 14, 2020
• Actual Study Completion Date: Feb 14, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: low dose rituximab this is a single-arm trial	Biological: rituximab; rituximab intravenously 100 mg every week for four doses; Other Names: Rituxan

Outcome Measures

Primary Outcome Measures

1. Incidence of the Composite Primary Outcome of Exacerbation or Refractory TTP [60 days]

   Exacerbation is recurring TTP ≤30 days after a Treatment Response (normal platelet count for 2 days) and discontinuation of plasma exchange. Refractory TTP is failure to achieve a Treatment Response by day 28, or failure to achieve a Durable Treatment Response (lasting at least 30 days) by day 60.

Secondary Outcome Measures

1. Incidence of Durable Treatment Response [60 days]

   Treatment Response is 2 consecutive days with platelet count ≥150, 000/µL Durable Treatment Response is a Treatment Response that persists for ≥30 days after discontinuation of plasma exchange and includes those with exacerbations

2. Number of Days to Durable Treatment Response [60 days]

   Median time to treatment response

3. Incidence of Relapse [Between 30 days and 2 years]

   Relapse is recurring TTP >30 days after Treatment Response

4. Months to Relapse [2 years]

   Mean months to relapse

5. Incidence of Death [2 years]

   Incidence of death will be assessed at 4 weeks, 1 year and 2 years

6. Treatment-related Adverse Events [2 years]

   Incidence, type and severity of treatment-related adverse events will be assessed. Patient reports, lab values, and physical exam were used to identify treatment-related adverse events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age 18 or greater

2. Diagnosis of suspected thrombotic thrombocytopenic purpura (TTP)

3. Platelet count of < 80,000 for newly diagnosed patients and < 120,000 for relapsed patients

4. Microangiopathic hemolytic anemia with RBC fragmentation

5. LDH >1 x ULN

6. Subjects who will receive treatment for TTP with plasma exchange

7. Subjects who have not started the 5th plasma exchange

8. Plasma ADAMTS13 activity <10%

Exclusion Criteria:

1. Treatment for TTP within the past 2 months

2. Severe active infection indicated by sepsis (requirement for pressors with or without positive blood cultures) or clinical evidence of enteric infection with E. coli O157:H7 or related organism

3. Currently under treatment for cancer (subjects with localized skin carcinoma will be accepted)

4. Microangiopathic hemolytic anemia due to a mechanical heart valve

5. Severe hypertension, as defined by systolic BP >180 AND diastolic BP >120, or papilledema

6. Organ or stem cell transplant

7. Use of calcineurin inhibitors (sirolimus, tacrolimus, cyclosporin A) within 6 months prior to diagnosis of TTP

8. Disseminated intravascular coagulation as defined by:

1. INR >2.0 (unrelated to anticoagulation, unresponsive to Vitamin K) or b. Fibrinogen <100 mg/dl

1. Pregnancy

2. Known congenital TTP.

3. Rituximab within the previous year.

4. HIV history or positive serology

5. History of hepatitis B or positive serology for HBsAg or Anti-HBc

6. Persistent or unexplained platelet count below 150,000/μL within 3 months of current TTP presentation

7. Hypersensitivities or allergies to murine and/or humanized antibodies

8. Current participation in trials of investigational therapies or devices, other than central catheters

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30322
2	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
3	Washington University	Saint Louis	Missouri	United States	63110
4	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Washington University School of Medicine
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Elaine M Majerus, MD, PhD, Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 18, 2018

More Information

Publications

• Froissart A, Buffet M, Veyradier A, Poullin P, Provôt F, Malot S, Schwarzinger M, Galicier L, Vanhille P, Vernant JP, Bordessoule D, Guidet B, Azoulay E, Mariotte E, Rondeau E, Mira JP, Wynckel A, Clabault K, Choukroun G, Presne C, Pourrat J, Hamidou M, Coppo P; French Thrombotic Microangiopathies Reference Center. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012 Jan;40(1):104-11. doi: 10.1097/CCM.0b013e31822e9d66.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01554514
• Other Study ID Numbers: 201108256-LDrituximab; 1U54HL112303-01
• First Posted: Mar 15, 2012
• Last Update Posted: Aug 17, 2021
• Last Verified: Aug 1, 2021

• Keywords provided by Washington University School of Medicine: ADAMTS13; Rituximab; Thrombotic thrombocytopenic purpura; TTP; Plasma exchange
• Additional relevant MeSH terms: Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic; Rituximab

Study Results

Participant Flow

Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
Period Title: Overall Study
STARTED	19
COMPLETED	17
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
Overall Participants	19
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	18 94.7%
>=65 years	1 5.3%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	46.7
Sex: Female, Male (Count of Participants)
Female	11 57.9%
Male	8 42.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	13 68.4%
White	6 31.6%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	19 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of the Composite Primary Outcome of Exacerbation or Refractory TTP
Description	Exacerbation is recurring TTP ≤30 days after a Treatment Response (normal platelet count for 2 days) and discontinuation of plasma exchange. Refractory TTP is failure to achieve a Treatment Response by day 28, or failure to achieve a Durable Treatment Response (lasting at least 30 days) by day 60.
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

Completed adjuvant riituximab therapy

Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
Measure Participants	17
Number with exacerbation	2 10.5%
Number with refractory TTP	0 0%

2. Secondary Outcome

Title	Incidence of Durable Treatment Response
Description	Treatment Response is 2 consecutive days with platelet count ≥150, 000/µL Durable Treatment Response is a Treatment Response that persists for ≥30 days after discontinuation of plasma exchange and includes those with exacerbations
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

Completed adjuvant rituximab therapy

Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
Measure Participants	17
Count of Participants [Participants]	17 89.5%

3. Secondary Outcome

Title	Number of Days to Durable Treatment Response
Description	Median time to treatment response
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

Completed adjuvant rituximab therapy

Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
Measure Participants	17
Median (Full Range) [days]	5

4. Secondary Outcome

Title	Incidence of Relapse
Description	Relapse is recurring TTP >30 days after Treatment Response
Time Frame	Between 30 days and 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
Measure Participants	17
Count of Participants [Participants]	5 26.3%

5. Secondary Outcome

Title	Months to Relapse
Description	Mean months to relapse
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Completed adjuvant rituximab

Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
Measure Participants	17
Mean (Full Range) [months]	17.3

6. Secondary Outcome

Title	Incidence of Death
Description	Incidence of death will be assessed at 4 weeks, 1 year and 2 years
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Completed adjuvant rituximab

Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
Measure Participants	17
Count of Participants [Participants]	1 5.3%

7. Secondary Outcome

Title	Treatment-related Adverse Events
Description	Incidence, type and severity of treatment-related adverse events will be assessed. Patient reports, lab values, and physical exam were used to identify treatment-related adverse events.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Completed adjuvant rituximab therapy

Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
Measure Participants	17
Number [treatment-related adverse events]	13

Adverse Events

Time Frame	2 years
Arm/Group Title	Low Dose Rituximab
Arm/Group Description	this is a single-arm trial rituximab: rituximab intravenously 100 mg every week for four doses
All Cause Mortality
	Low Dose Rituximab
	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)
Serious Adverse Events
	Low Dose Rituximab
	Affected / at Risk (%)	# Events
Total	10/17 (58.8%)
Blood and lymphatic system disorders
Relapsed Thrombotic Thrombocytopenia Purpura	2/17 (11.8%)	4
Cardiac disorders
heart failure	1/17 (5.9%)	1
Atrial Fibrillation with Rapid Ventricular Response	1/17 (5.9%)	1
chest pain, palpitations, shortness of breath	1/17 (5.9%)	2
Gastrointestinal disorders
Lower Gastrointestinal Bleed	1/17 (5.9%)	1
General disorders
multi-system organ failure	1/17 (5.9%)	1
neck pain, abdominal distention	1/17 (5.9%)	1
fever	2/17 (11.8%)	2
Infections and infestations
sepsis, gram-negative bacterial infection	1/17 (5.9%)	1
fever, central line complication, bacteremia	1/17 (5.9%)	1
cellulitis	1/17 (5.9%)	1
Pancreatitis (presenting symptom abdominal pain)	1/17 (5.9%)	1
Investigations
thrombocytopenia	1/17 (5.9%)	2
Respiratory, thoracic and mediastinal disorders
shock, acute respiratory failure	1/17 (5.9%)	1
Hyper-somnolence with hypoxia and hypotension	1/17 (5.9%)	1
Other (Not Including Serious) Adverse Events
	Low Dose Rituximab
	Affected / at Risk (%)	# Events
Total	17/19 (89.5%)
Blood and lymphatic system disorders
anemia	7/17 (41.2%)	12
cervical lymphadenopathy	1/17 (5.9%)	1
Cardiac disorders
heart palpitations	1/17 (5.9%)	1
tachycardia	1/19 (5.3%)	1
Eye disorders
blurred vision	1/19 (5.3%)	1
double vision	1/19 (5.3%)	1
floaters	1/19 (5.3%)	1
Gastrointestinal disorders
dyspepsia	1/17 (5.9%)	1
constipation	3/17 (17.6%)	3
diarrhea	3/17 (17.6%)	3
hemorrhoids	1/19 (5.3%)	1
hemorrhoidal hemorrhage	1/19 (5.3%)	1
gingival bleeding	1/19 (5.3%)	2
GI Disorder	1/19 (5.3%)	1
nausea	1/19 (5.3%)	4
vomiting	1/19 (5.3%)	2
gastro-esophageal reflux disease	1/19 (5.3%)	1
General disorders
fatigue	3/17 (17.6%)	3
swelling	2/17 (11.8%)	2
fever	2/17 (11.8%)	2
pain - lips	1/17 (5.9%)	1
Edema to face	1/17 (5.9%)	1
flu-like symptoms	2/19 (10.5%)	2
non-cardiac chest pain	1/19 (5.3%)	1
Immune system disorders
anaphylaxis	1/19 (5.3%)	1
Infections and infestations
uterine infection	1/19 (5.3%)	1
vaginal discharge	1/19 (5.3%)	1
endometritis	1/19 (5.3%)	1
Injury, poisoning and procedural complications
Fall	1/19 (5.3%)	1
Investigations
thrombocytopenia	4/17 (23.5%)	6
weight gain	3/17 (17.6%)	3
elevated creatinine	2/17 (11.8%)	2
Lymphocyte decrease	2/17 (11.8%)	5
ALT Elevation	2/19 (10.5%)	5
AST elevation	1/19 (5.3%)	3
Metabolism and nutrition disorders
decreased appetite	1/17 (5.9%)	1
hypomagnesemia	1/17 (5.9%)	1
hyperglycemia	2/17 (11.8%)	4
hypocalcemia	1/17 (5.9%)	1
hypernatremia	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
muscle pain/myalgia	2/19 (10.5%)	2
Nervous system disorders
dizziness	2/17 (11.8%)	3
headache	4/17 (23.5%)	5
left hand numbness	1/17 (5.9%)	1
neuropathy	1/19 (5.3%)	1
paresthesia - hands	1/19 (5.3%)	1
Psychiatric disorders
sleep disturbances/insomnia	2/17 (11.8%)	2
depression	1/17 (5.9%)	1
delirium	1/17 (5.9%)	1
anxiety	1/17 (5.9%)	3
hallucinations	1/19 (5.3%)	1
Renal and urinary disorders
hematuria	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
rhinorrhea	1/17 (5.9%)	1
cough	4/17 (23.5%)	4
nasal congestion	1/17 (5.9%)	1
pneumothorax	1/17 (5.9%)	1
pneumonia	1/17 (5.9%)	1
shortness of breath	1/17 (5.9%)	1
dyspnea	1/19 (5.3%)	1
Skin and subcutaneous tissue disorders
ulcer to right nostril	1/17 (5.9%)	1
acne	1/17 (5.9%)	1
pruritis	3/17 (17.6%)	4
hives	1/17 (5.9%)	7
Social circumstances
menopause	1/19 (5.3%)	1
hot flashes	1/19 (5.3%)	1
night sweats	1/19 (5.3%)	1
Vascular disorders
hypertension	3/17 (17.6%)	3

Limitations/Caveats

[Not Specified]

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.