Thrombotic MicroangiopathyNCT02604420
Identification and Treatment of Thrombotic Microangiopathies in Allogeneic Stem Cell Transplants
An observational study of Thrombotic Microangiopathy and Disorder Related to Bone Marrow Transplantation, run by Weill Medical College of Cornell University at 1 site in United States.
Trial summary
Mortality in the major thrombotic microangiopathies (TMAs), TTP and aHUS, exceeds 90% unless rapidly diagnosed and appropriately treated. TMAs complicate 10-20% of allogeneic bone marrow hematopoietic stem cell transplants (alloHSCT), conveying inferior survival. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Thrombotic Microangiopathy, Disorder Related to Bone Marrow Transplantation
- What is being tested?
- eculizumab
- Type of treatment
- Vaccines, Injection or infusion
- How many people
- 200 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2014to 28 Mar 2018
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Adults (age 18-65) undergoing an allogeneic hematopoietic stem cell transplant
Who may be able to join
- participants scheduled to undergo an allogeneic stem cell transplant
- willing to consent to genetic testing
Who cannot join
- pregnant women
- nursing mothers
- women of child-bearing potential who are unwilling to use medically accepted methods of contraception
- patients with known contraindications to use of eculizumab
- patients who cannot tolerate plasma exchange
Trial locations and contacts
1 site in 1 country.
United States1 site
New York Presbyterian Hospital
New York, New York, 10021
About this study
Official title: Identification of the Pathogenesis of Thrombotic Microangiopathy in the Allo Stem Cell Transplant Setting in Adults
Mortality in the major thrombotic microangiopathies (TMAs), TTP and aHUS, exceeds 90% unless rapidly diagnosed and appropriately treated. TMAs complicate 10-20% of allogeneic bone marrow hematopoietic stem cell transplants (alloHSCT), conveying inferior survival. Multiple etiologies have been proposed for these transplant-associated TMAs (TA-TMAs), but once infection, graft vs. host disease (GvHD), and drug effects have been ruled out, most are treated as TTP-like disorders using plasma exchange (PEx). But PEx has no impact on mortality in this setting. Clear definition of the pathophysiology of the TA-TMAs is required to guide effective treatment. Investigators hypothesize that an aHUS-type TMA, related to dysregulation of the alternative complement pathway, is involved and will be characterized by elevated plasma levels of C5b-9 and detectable C5b-9 deposition in bone marrow sinusoidal vessels. Investigators further hypothesize that treatment with inhibitors of terminal complement components will reverse the TMA in vivo, and block endothelial cell damage in our in vitro model systems. The data investigators generate from this observational study of TA-TMAs should enable prediction of their development prior to overt clinical manifestations, and guide appropriate therapy.
Read the detailed description
Investigators plan to enroll 120 adult patients who are undergoing an allogeneic hematopoietic stem cell transplant and follow them serially for one year. Investigators will harvest and store at -80oC plasma and PBMCs, and collect bone marrow core biopsy specimens on all individuals at baseline, days 28, 100, 190, 365 post-transplant, and at time of relapse of primary disease relapse or TMA development. These time points, bone marrow procedures, and blood draws are part of the ordinary and customary followup of any allogeneic HSCT patient at our institution. With these patient samples investigators will:
- Determine the incidence of all TMAs fitting the criteria of a Coombs negative hemolytic anemia, thrombocytopenia (25% decrease from baseline) and elevated (2x baseline) LDH, with schistocytes and organ system involvement (typically increased creatinine or new microscopic hematuria or proteinuria)
- Determine the incidence of an aHUS-like TMA, i.e., a TMA characterized by ADAMTS13 activity in plasma >5% with clinical and laboratory findings which persists after stopping their calcineurin or mTOR inhibitor for one half life (3-7 days, depending on the drug), and ruling out or treating an underlying systemic infection or GvHD.
- Determine complement component activation, proinflammatory cytokine profile, and baseline complement mutations. This will include ELISA-based measures of plasma C5a, C5b-9, MASP-1-3, tumor necrosis factor(TNF)-α, and interferon-γ, and pre-transplant complement mutational analysis .
- Assay participants plasma for the ability to induce injury in primary human microvascular endothelial cells (MVEC), and the ability of an anti-C5 monoclonal antibody (mAb) (Alexion, eculizumab (Soliris)) and anti-MASP2 (Omeros, OMS721) mAb, to block these changes in the investigators' established model.
- Define the degree of C5b-9 deposition in sinusoidal CD34+ endothelial cells by immunohistochemistry, (IHC) examining marrow core biopsies collected at each patient visit and at time of TMA development.
- Correlate changes in plasma biomarkers, marrow sinusoidal C5b-9 deposition, and the in vitro plasma-MVEC injury model with treatment interventions and treatment outcomes, chosen by the transplant attending of record in this observational cohort.
- Being tested
- eculizumab
- Medical subject headings
- Thrombotic Microangiopathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
eculizumabDrug
Also called Soliris
| Study group | Role | What they receive |
|---|---|---|
| Transplant, no TMA | Adult patients who undergo an allogeneic hematopoietic stem cell transplant but do not meet the criteria for a thrombotic microangiopathy in the one year follow up period. No interventions anticipated. | |
| Transplant, +TMA | Adult patients who undergo an allogeneic hematopoietic stem cell transplant and meet the criteria for a thrombotic microangiopathy in the one year follow up period. Possible interventions include observation, treatment of an underlying infection or GvHD, use of plasma exchange, or use of anti-complement therapy (eculizumab or other anti-complement drug). Eculizumab is used as a 900mg intravenous infusion over 35 minutes, given weekly for 4 weeks, then 1200mg every other week. Patients must be vaccinated against meningococcus 2 weeks before starting drug or, if that is not feasible because of the physician's assessment of the severity of the TMA, given prophylactic antibiotics for the 2 week period before immunization has taken hold. Receives: Drug: eculizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with thrombotic microangiopathy occurring in the allogeneic stem cell transplant setting
Per protocol a thrombotic microangiopathy is defined as development of:
- increase in number of schistocytes per high power microscopic field from baseline
- increase in baseline level of anemia, measured by hemoglobin decline, which must be Coombs negative
- unexplained doubling from baseline of serum LDH
Measured: 2 years
Number of participants with allogeneic stem cell transplant-linked TMA persisting after control of infection, GvHD and altering medications
Investigators will determine the number of participants with TMAs that persist after:
- stopping calcineurin and mTOR inhibitor use for one half-life (3-7 days, depending on drug)
- treating an underlying infection, if identified
- suppressing new GvHD, if present
Measured: 2 years
Secondary outcomes (1)
Number of participants with allogeneic stem cell transplant-linked TMA persisting after control of infection, GvHD and altering medications responsive to intervention
This is an observational study. No interventions are specified, by standards of practice could include supportive care, plasma exchange, use of eculizumab (Soliris)
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Nov 2015 (estimated)
- Study startSep 2014
- Primary completion28 Mar 2018
- Study completion28 Mar 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Thrombotic MicroangiopathyStudies of the same condition, open and under way.
- More trials run by Weill Medical College of Cornell UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 200 participants (actual)
Sponsor and investigators
- Lead sponsor
- Weill Medical College of Cornell University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jeffrey Laurence, MD, Principal investigator, Weill Medical College of Cornell University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02604420
- Sponsor's protocol ID
- 1403014892
- Status last verified
- Mar 2018
- First submitted
- 15 Oct 2015
- Last updated
- 30 Mar 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No: No plan to share IPD.
Publications
Chapin J, Shore T, Forsberg P, Desman G, Van Besien K, Laurence J. Hematopoietic transplant-associated thrombotic microangiopathy: case report and review of diagnosis and treatments. Clin Adv Hematol Oncol. 2014 Sep;12(9):565-73.
PubMed 25654478
Study at a glance
From the registry record, last updated by the sponsor on 30 Mar 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identification of the Pathogenesis of Thrombotic Microangiopathy in the Allo Stem Cell Transplant Setting in Adults
- ClinicalTrials.gov ID
- NCT02604420
- Acronym / sponsor ID
- 1403014892
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 200 participants (actual)
- Lead sponsor
- Weill Medical College of Cornell UniversityUniversity, hospital or other
- Study start
- Sep 2014 (actual)
- Primary completion
- 28 Mar 2018 (actual)
- Study completion
- 28 Mar 2018 (actual)
- First posted
- 13 Nov 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Mortality in the major thrombotic microangiopathies (TMAs), TTP and aHUS, exceeds 90% unless rapidly diagnosed and appropriately treated. TMAs complicate 10-20% of allogeneic bone marrow hematopoietic stem cell transplants (alloHSCT), conveying inferior survival. Multiple etiologies have been proposed for these transplant-associated TMAs (TA-TMAs), but once infection, graft vs. host disease (GvHD), and drug effects have been ruled out, most are treated as TTP-like disorders using plasma exchange (PEx). But PEx has no impact on mortality in this setting. Clear definition of the pathophysiology of the TA-TMAs is required to guide effective treatment. Investigators hypothesize that an aHUS-type TMA, related to dysregulation of the alternative complement pathway, is involved and will be characterized by elevated plasma levels of C5b-9 and detectable C5b-9 deposition in bone marrow sinusoidal vessels. Investigators further hypothesize that treatment with inhibitors of terminal complement components will reverse the TMA in vivo, and block endothelial cell damage in our in vitro model systems. The data investigators generate from this observational study of TA-TMAs should enable prediction of their development prior to overt clinical manifestations, and guide appropriate therapy.
Detailed description
Investigators plan to enroll 120 adult patients who are undergoing an allogeneic hematopoietic stem cell transplant and follow them serially for one year. Investigators will harvest and store at -80oC plasma and PBMCs, and collect bone marrow core biopsy specimens on all individuals at baseline, days 28, 100, 190, 365 post-transplant, and at time of relapse of primary disease relapse or TMA development. These time points, bone marrow procedures, and blood draws are part of the ordinary and customary followup of any allogeneic HSCT patient at our institution. With these patient samples investigators will:
- Determine the incidence of all TMAs fitting the criteria of a Coombs negative hemolytic anemia, thrombocytopenia (25% decrease from baseline) and elevated (2x baseline) LDH, with schistocytes and organ system involvement (typically increased creatinine or new microscopic hematuria or proteinuria)
- Determine the incidence of an aHUS-like TMA, i.e., a TMA characterized by ADAMTS13 activity in plasma >5% with clinical and laboratory findings which persists after stopping their calcineurin or mTOR inhibitor for one half life (3-7 days, depending on the drug), and ruling out or treating an underlying systemic infection or GvHD.
- Determine complement component activation, proinflammatory cytokine profile, and baseline complement mutations. This will include ELISA-based measures of plasma C5a, C5b-9, MASP-1-3, tumor necrosis factor(TNF)-α, and interferon-γ, and pre-transplant complement mutational analysis .
- Assay participants plasma for the ability to induce injury in primary human microvascular endothelial cells (MVEC), and the ability of an anti-C5 monoclonal antibody (mAb) (Alexion, eculizumab (Soliris)) and anti-MASP2 (Omeros, OMS721) mAb, to block these changes in the investigators' established model.
- Define the degree of C5b-9 deposition in sinusoidal CD34+ endothelial cells by immunohistochemistry, (IHC) examining marrow core biopsies collected at each patient visit and at time of TMA development.
- Correlate changes in plasma biomarkers, marrow sinusoidal C5b-9 deposition, and the in vitro plasma-MVEC injury model with treatment interventions and treatment outcomes, chosen by the transplant attending of record in this observational cohort.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Transplant, no TMA | – | –Adult patients who undergo an allogeneic hematopoietic stem cell transplant but do not meet the criteria for a thrombotic microangiopathy in the one year follow up period. No interventions anticipated. |
| Transplant, +TMA | – | Drug: eculizumabAdult patients who undergo an allogeneic hematopoietic stem cell transplant and meet the criteria for a thrombotic microangiopathy in the one year follow up period. Possible interventions include observation, treatment of an underlying infection or GvHD, use of plasma exchange, or use of anti-complement therapy (eculizumab or other anti-complement drug). Eculizumab is used as a 900mg intravenous infusion over 35 minutes, given weekly for 4 weeks, then 1200mg every other week. Patients must be vaccinated against meningococcus 2 weeks before starting drug or, if that is not feasible because of the physician's assessment of the severity of the TMA, given prophylactic antibiotics for the 2 week period before immunization has taken hold. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Adults (age 18-65) undergoing an allogeneic hematopoietic stem cell transplant
Key inclusion criteria (2 listed)
- participants scheduled to undergo an allogeneic stem cell transplant
- willing to consent to genetic testing
Key exclusion criteria (5 listed)
- pregnant women
- nursing mothers
- women of child-bearing potential who are unwilling to use medically accepted methods of contraception
- patients with known contraindications to use of eculizumab
- patients who cannot tolerate plasma exchange
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| eculizumabAlso: Soliris | Drug | Transplant, +TMA |
Primary outcome
Number of participants with thrombotic microangiopathy occurring in the allogeneic stem cell transplant setting
Time frame: 2 years
Per protocol a thrombotic microangiopathy is defined as development of: * increase in number of schistocytes per high power microscopic field from baseline * increase in baseline level of anemia, measured by hemoglobin decline, which must be Coombs negative * unexplained doubling from baseline of serum LDH
Number of participants with allogeneic stem cell transplant-linked TMA persisting after control of infection, GvHD and altering medications
Time frame: 2 years
Investigators will determine the number of participants with TMAs that persist after: * stopping calcineurin and mTOR inhibitor use for one half-life (3-7 days, depending on drug) * treating an underlying infection, if identified * suppressing new GvHD, if present
1 secondary outcome
Number of participants with allogeneic stem cell transplant-linked TMA persisting after control of infection, GvHD and altering medications responsive to intervention
Time frame: 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Mar 2018.
- Results publication: PubMed 25654478Chapin J, Shore T, Forsberg P, Desman G, Van Besien K, Laurence J. Hematopoietic transplant-associated thrombotic microangiopathy: case report and review of diagnosis and treatments. Clin Adv Hematol Oncol. 2014 Sep;12(9):565-73.
- Individual participant dataSharing planned: No. No plan to share IPD.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeffrey Laurence, MD principal investigator
Weill Medical College of Cornell University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Thrombotic Microangiopathy and Disorder Related to Bone Marrow Transplantation, run by Weill Medical College of Cornell University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Mar 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants with thrombotic microangiopathy occurring in the allogeneic stem cell transplant setting (time frame: 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02604420, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Mar 2018.