Risk Stratification-directed NAC for Prevention of Poor Hematopoietic Reconstitution

September 13, 2021 updated by: Xiao-Jun Huang, Peking University People's Hospital

Risk Stratification-directed N-acetyl-L-cysteine for Prevention of Poor Hematopoietic Reconstitution After Unmanipulated Haploidentical Stem Cell Transplantation--an Open-label, Randomized, Controlled, Clinical Trial

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment of malignant hematopoietic diseases. However, poor hematopoietic reconstitution including poor graft function (PGF) and prolonged isolated thrombocytopenia (PT), remains a life-threatening complication after allo-HSCT. Especially with the increasing use of haploidentical allo-HSCT (haplo-HSCT) in the past ten years, PGF and PT have become growing obstacles contributing to high morbidity and mortality after allo-HSCT. Due to the limited mechanism studies, the clinical management of PGF and PT is challenging.

Recent prospective case-control studies reported that the reduced and dysfunctional bone marrow (BM) endothelial cells (ECs) after allo-HSCT are involved in the pathogenesis of PGF and PT. Moreover, in vitro treatment with N-acetyl-L-cysteine (NAC) could enhance the defective hematopoietic stem cell (HSC) function through repairing the dysfunctional BM ECs of PGF and PT patients. The investigators performed a small-scale pilot cohort study and saw encouraging clinical results that oral administration with NAC could partially repair the dysfunctional BM ECs and improve megakaryocytopoiesis in PT patients, which suggests that NAC is a promising drug in PT patients after allo-HSCT. In addition, prior prospective trial of the investigators suggests that BM ECs<0.1% pre-HSCT is the risk factor for occurrence of the PGF and PT two months following allo-HSCT. Previous single-arm clinical cohort studies of the investigators showed that prophylactic use of NAC before allo-HSCT reduced the incidence of poor hematopoietic reconstitution after allo-HSCT in patients with ECs <0.1% pre-HSCT.

Therefore, the investigators designed the study with acute leukemia patients who will be scheduled to receive haplo-HSCT. The patients who are in the first complete remission at time of haplo-transplant will be enrolled in the study. Exclusive criteria are bronchila asthma and NAC allergy. The enrolled patients were risk-stratified into BM ECs≥0.1% group (low-risk group) and BM ECs<0.1% group (high-risk group). Patients in high-risk group (ECs<0.1%) will be randomized to 1 of 2 arms: (a) NAC 400 mg three times per day from 14 days pre-HSCT to 2 months post-HSCT, (b) No-NAC concurrent control according to a 2:1 schedule. The aim of the trail is to assess the effects of NAC for prevention of poor hematopoietic reconstitution in patients with acute leukemia undergoing haplo-HSCT.

Study Overview

Status

Active, not recruiting

Intervention / Treatment

Detailed Description

This study is designed as a phase III, open-label, randomized study assessing the safety and efficacy of NAC (400 mg, orally, three times daily) versus no-NAC control for prevention of poor hematopoietic reconstitution in patients with acute leukemia undergoing haploidentical HSCT in a 2:1 ratio. The study will consist of three phases: a pre-randomization phase, a treatment phase, and an observational follow-up phase.

The screening period: Patients will be screened during a 1 week screening period prior to entering the trial to allow for the collection of BM samples to evaluate the quantity and function of BM ECs at 21-14 days before HSCT. The enrolled patients were risk-stratified into BM ECs≥0.1% group (low-risk group) and BM ECs<0.1% group (high-risk group). Approximately 126 patients with BM EC <0.1% at day-14 pre-HSCT (84 patients in NAC treatment arm and 42 patients in control arm) will be randomized in a 2:1 ratio to 1 of 2 arms: (a) NAC 400 mg three times per day, (b) No-NAC concurrent control.

The treatment phase: Study medication will be administered orally, 400 mg three times daily from -14 days pre-HSCT to +2 months post-HSCT. All patients should continue their pre study dose of NAC throughout trial participation. Following randomization, patients will have 3 hospitalized or at-clinic trial visits at day 0 before-HSCT and 1, 2 months post-HSCT to evaluate efficacy, safety, tolerability and compliance with study medication. Patients will be contacted by trial site staff on a monthly basis between visits beginning with day 0.

The observational follow-up phase: Upon completion of the trial participation phase all eligible patients will enter an open label follow-up phase. Clinic visits will occur every 3 months (± 1 week).

Patients will have a pretreatment bone marrow aspiration conducted and have a follow up bone marrow aspiration conducted at day0 before-HSCT and 1, and 2 months post-HSCT. All patients who complete or discontinue from the trial, for any reason, will have a follow up visit, 4 weeks after their last dose of study medication. The primary outcome is the incidence of PGF and PT at 2 months after HSCT, as well as the safety. Secondary endpoints included cumulative incidences of relapse (CIR), acute graft-versus-host disease (aGVHD), non-relapse mortality (NRM), overall survival (OS), disease free survival (DFS), the related laboratory evaluation of ECs and HSC in BM microenvironment, etc.

Study Type

Interventional

Enrollment (Actual)

130

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Beijing, China, 100044
        • Peking University People's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

15 years to 60 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Acute leukemia in the first complete remission (CR1) at time of haplo- transplant.
  • Age ≥ 15 years.
  • Contraception: Female patients of childbearing potential must use ≥ 1 effective (≤ 1% failure rate) method of contraception during the trial and until the end of treatment visit.
  • Must provide written informed consent and agree to comply with the trial protocol.

Exclusion Criteria:

  • History or presence of allergy to NAC.
  • History or presence of clinically concerning Bronchial asthma.
  • Non-CR1 leukemia at time of transplant.
  • Patients undergoing transplant from donors other than haploidentical relatives.
  • Patients who have previously participated in a clinical trial of NAC.
  • If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment arm
NAC 400 mg three times per day from -14D pre-HSCT to +2 months
NAC 400 mg three times per day from -14D pre-HSCT to +2 months post-HSCT
Other Names:
  • NAC
No Intervention: Control arm
No-NAC concurrent control according to a 2:1 schedule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The incidence of poor hematopoietic reconstitution at 2 months post-HSCT
Time Frame: 2 months post-HSCT
The incidence of poor hematopoietic reconstitutio at 2 months post-HSCT
2 months post-HSCT

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cumulative incidences of relapse at one year post-HSCT
Time Frame: 1 year after transplantation
Cumulative incidences of relapse at one year post-HSCT.
1 year after transplantation
Cumulative incidences of acute graft-versus-host disease for 100 days post-HSCT
Time Frame: 100 days after transplantation
Cumulative incidences of acute graft-versus-host disease for 100 days post-HSCT
100 days after transplantation
Non-relapse mortality during 1 year post-HSCT
Time Frame: 1 year after transplantation
Non-relapse mortality during 1 year post-HSCT
1 year after transplantation
Overall survival during 1 year post-HSCT
Time Frame: 1 year after transplantation
Overall survival during 1 year post-HSCT
1 year after transplantation
Disease free survival during 1 year post-HSCT
Time Frame: 1 year after transplantation
Disease free survival during 1 year post-HSCT
1 year after transplantation
Number of participants with treatment-related adverse events during oral administration of NAC.
Time Frame: 14 days pre-HSCT to 2 months post-HSCT.
Number of participants with treatment-related adverse events during oral administration of NAC.
14 days pre-HSCT to 2 months post-HSCT.
Effect of NAC on ECs percentage at 0 day pre-HSCT, 1 month, 2 months post-HSCT
Time Frame: 0 day pre-HSCT, 1 month, 2 months post-HSCT
ECs percentages at 0 day pre-HSCT, 1 month, 2 months post-HSCT
0 day pre-HSCT, 1 month, 2 months post-HSCT
Effect of NAC on HSCs percentagesat 0 day pre-HSCT, 1 month, 2 months post-HSCT
Time Frame: 0 day pre-HSCT, 1 month, 2 months post-HSCT
HSCs percentages at 0 day pre-HSCT, 1 month, 2 months post-HSCT
0 day pre-HSCT, 1 month, 2 months post-HSCT
Effect of NAC on MKs numbers at 0 day pre-HSCT, 1 month, 2 months post-HSCT
Time Frame: 0 day pre-HSCT, 1 month, 2 months post-HSCT
MKs numbers at 0 day pre-HSCT, 1 month, 2 months post-HSCT
0 day pre-HSCT, 1 month, 2 months post-HSCT
Incidence of viral infection until 100 days post-HSCT.
Time Frame: 100 days post-HSCT.
Incidence of viral infection until 100 days post-HSCT.
100 days post-HSCT.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Xiao-Jun Huang, MD, Peking University People's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2018

Primary Completion (Actual)

September 5, 2021

Study Completion (Anticipated)

October 1, 2024

Study Registration Dates

First Submitted

April 3, 2019

First Submitted That Met QC Criteria

May 29, 2019

First Posted (Actual)

May 30, 2019

Study Record Updates

Last Update Posted (Actual)

September 14, 2021

Last Update Submitted That Met QC Criteria

September 13, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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