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Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients
Phase 2 trial testing Immunosuppression withdrawal in Liver Transplant Recipients in 161 participants. Completed in 11 June 2018.
| Lead sponsor | National Institute of Allergy and Infectious Diseases (NIAID) |
|---|---|
| Phase | Phase 2 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | na |
| Design | single group |
| Masking | none |
| Primary purpose | treatment |
| Enrollment | 161 |
| Start date | 14 August 2012 |
| Primary completion | 31 March 2016 |
| Estimated completion | 11 June 2018 |
| Sites | 12 locations across Canada, United States |
National Institute of Allergy and Infectious Diseases (NIAID)
Under 18, any sex, with Liver Transplant Recipients or Liver Transplantation. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
Number of participants that are operationally tolerant, defined as those who successfully withdraw from immunosuppression and maintain normal allograft status as assessed by liver biopsy and liver tests 12 months after complete immunosuppression withdrawal.
| Group | Value | 95% CI |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | 33 |
This composite endpoint is comprised of clinical complications related to immunosuppression withdrawal and is defined as the occurrence of any of the following: death or graft loss, histologic evidence of refractory acute rejection or biopsy confirmed chronic rejection (CR).
| Group | Value | 95% CI |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | 0 |
The median time (in days) from start of withdrawal from immunosuppression drugs to increasing or re-starting immunosuppression.
| Group | Value | 95% CI |
|---|---|---|
| Participants That Increased IS Dosing or Restarted IS | 204 | 167 – 246 |
The median time (in weeks) from biopsy proven rejection to resolution of rejection defined as both liver function tests Alanine Aminotransferase (ALT) and Gamma-Glutamyl Transferase (GGT) returning to ≤ 1.5 the baseline values.
| Group | Value | 95% CI |
|---|---|---|
| Participants That Experienced BPAR | 13 | 8.4 – 16.6 |
Number of biopsies that were diagnosed as histologic acute rejection in participants who initiated immunosuppression withdrawal by severity of rejection episode. Rejection severity (mild, moderate, severe) is based on the Banff global assessment grade according to the central pathology reading of the liver biopsy. Mild severity criteria: rejection infiltrate in a minority of triads that is generally mild and confined within the portal spaces. Moderate rejection criteria: rejection infiltrate expanding most or all of the triads. Severe rejection criteria: rejection infiltrate expanding most or
| Group | Value | 95% CI |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | 43 |
| Group | Value | 95% CI |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | 7 |
| Group | Value | 95% CI |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | 0 |
The clinical severity of acute rejection was descriptively analyzed using hierarchical categories, as follows: * Dose increase: Increase in IS dose and/or frequency but to a level less than the regimen at study entry, prior to initiating ISW * Reinstitution: Returning to the regimen at study entry, prior to ISW * Intensification: Increased IS dose compared with the dose at study entry, prior to ISW * Conversion: Change to different IS drug * Addition: Initiation of a second IS drug; * Corticosteroids: Administration of any intravenous or oral corticosteroids * Antibody (Ab) treatment: Adminis
| Group | Value | 95% CI |
|---|---|---|
| Participants With Adverse Events of BPAR or Clinical Rejection | 0.068 | 0.025 – 0.143 |
| Group | Value | 95% CI |
|---|---|---|
| Participants With Adverse Events of BPAR or Clinical Rejection | 0.261 | 0.173 – 0.366 |
| Group | Value | 95% CI |
|---|---|---|
| Participants With Adverse Events of BPAR or Clinical Rejection | 0.227 | 0.145 – 0.329 |
| Group | Value | 95% CI |
|---|---|---|
| Participants With Adverse Events of BPAR or Clinical Rejection | 0.011 | 0 – 0.062 |
| Group | Value | 95% CI |
|---|---|---|
| Participants With Adverse Events of BPAR or Clinical Rejection | 0.023 | 0 – 0.08 |
| Group | Value | 95% CI |
|---|---|---|
| Participants With Adverse Events of BPAR or Clinical Rejection | 0.364 | 0.264 – 0.473 |
| Group | Value | 95% CI |
|---|---|---|
| Participants With Adverse Events of BPAR or Clinical Rejection | 0 | 0 – 0.041 |
Reasons participants discontinued immunosuppression withdrawal, such as Biopsy Proven Acute Rejection, Chronic Rejection, Clinical Rejection, Death, Pregnancy, etc.). Only the root cause for discontinuation for each subject is presented in these results if multiple events led to discontinuation of immunosuppression withdrawal.
| Group | Value | 95% CI |
|---|---|---|
| Participants That Discontinued Immunosuppression Withdrawal | 30 |
| Group | Value | 95% CI |
|---|---|---|
| Participants That Discontinued Immunosuppression Withdrawal | 3 |
The impact of ISW on allograft fibrosis using the Ishak scoring system to measure the change in fibrosis from the screening liver biopsy to the end-of-study (month-48) liver biopsy. In the Ishak histologic scoring system, the higher the score/stage, the more fibrosis: Scores range from 0 to 6, with 6 representing the most fibrosis: 0=No fibrosis; 1=Fibrous expansion of some portal areas, with or without short fibrous septa; 2=Fibrous expansion of most portal areas, with or without short fibrous septa; 3=Fibrous expansion of most portal areas, with occasional portal to portal bridging; 4=Fibro
| Group | Value | 95% CI |
|---|---|---|
| Participants That Had Both Screening and End-of-Study Biopsies | 18 | |
| Participants That Had Both Screening and End-of-Study Biopsies | 43 | |
| Participants That Had Both Screening and End-of-Study Biopsies | 19 | |
| Participants That Had Both Screening and End-of-Study Biopsies | 3 |
Median participant duration of operational tolerance. Duration of operational tolerance is defined as the number of days that participants are not taking immunosuppression medications.
| Group | Value | 95% CI |
|---|---|---|
| Participants Deemed Tolerant by Trial Definition | 1209.5 | 1205 – 1214 |
The mean percent of immunosuppression (IS) dose reduction from baseline to the time of immunosuppression withdrawal failure. Immunosuppression withdrawal failure is defined as any incidence of increasing immunosuppression medications instead of completing withdrawal.
| Group | Value | 95% CI |
|---|---|---|
| Participants That Discontinued Immunosuppression Withdrawal | -76.1 | -80.59 – -71.63 |
Change of immunosuppression (IS) dose from baseline to end of study for all participants not deemed tolerant by the trial definition either due to discontinuing IS withdrawal or completing withdrawal but not meeting the criteria for tolerance on the primary endpoint biopsy assessment.
| Group | Value | 95% CI |
|---|---|---|
| Participants Not Deemed Tolerant by the Trial Definition | 0.4 | -21.12 – 21.98 |
Health related quality of life was measured by the PedsQL 4.0 Generic Core scale, the Multidimensional Fatigue scale, and the PedsQL 3.0 Transplant module. Change was calculated as the difference between the questionnaire completed at the initiation of withdrawal and at month 36 for the total generic score, the total fatigue score, and total transplant score. This change was calculated separately for tolerant and non-tolerant subjects. Each score ranges from 0-100, with a higher score indicating a better quality of life.
| Group | Value | 95% CI |
|---|---|---|
| Participants Were Operationally Tolerant | 3.4 | -0.8 – 7.7 |
| Participants Who Were Not Operationally Tolerant | 1.2 | -2.1 – 4.5 |
| Group | Value | 95% CI |
|---|---|---|
| Participants Were Operationally Tolerant | 5.0 | 1.2 – 8.8 |
| Participants Who Were Not Operationally Tolerant | 2.0 | -3.9 – 7.8 |
| Group | Value | 95% CI |
|---|---|---|
| Participants Were Operationally Tolerant | 5.7 | 1.7 – 9.8 |
| Participants Who Were Not Operationally Tolerant | 0.9 | -2.5 – 4.2 |
Time frame: Time of enrollment through end of study participation (e.g., up to 48 months).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | All Enrolled Participants |
|---|---|---|
| Transplant rejection | Immune system disorders | — |
| Bile duct stenosis | Hepatobiliary disorders | — |
| Cholangitis | Hepatobiliary disorders | — |
| Gastroenteritis | Infections and infestations | — |
| Gastroenteritis viral | Infections and infestations | — |
| Viral infection | Infections and infestations | — |
| Procedural pain | Injury, poisoning and procedural complications | — |
| Suicidal ideation | Psychiatric disorders | — |
| Menorrhagia | Reproductive system and breast disorders | — |
| Asthma | Respiratory, thoracic and mediastinal disorders | — |
| Abdominal pain | Gastrointestinal disorders | — |
| Intestinal obstruction | Gastrointestinal disorders | — |
| Cellulitis | Infections and infestations | — |
| Pharyngitis | Infections and infestations | — |
| Pneumonia | Infections and infestations | — |
| Post procedural cellulitis | Infections and infestations | — |
| Varicella | Infections and infestations | — |
| Post procedural bile leak | Injury, poisoning and procedural complications | — |
| Subdural haematoma | Injury, poisoning and procedural complications | — |
| Ulna fracture | Injury, poisoning and procedural complications | — |
| Liver function test abnormal | Investigations | — |
| Dehydration | Metabolism and nutrition disorders | — |
| Grand mal convulsion | Nervous system disorders | — |
| Aggression | Psychiatric disorders | — |
| Depression | Psychiatric disorders | — |
| Reaction | System | All Enrolled Participants |
|---|---|---|
| Transplant rejection | Immune system disorders | — |
| Nasopharyngitis | Infections and infestations | — |
| Liver function test abnormal | Investigations | — |
| Gastroenteritis viral | Infections and infestations | — |
| Upper respiratory tract infection | Infections and infestations | — |
| Viral infection | Infections and infestations | — |
| Abdominal pain | Gastrointestinal disorders | — |
| Headache | Nervous system disorders | — |
| Diarrhoea | Gastrointestinal disorders | — |
| Influenza like illness | General disorders | — |
| Pharyngitis streptococcal | Infections and infestations | — |
| Cough | Respiratory, thoracic and mediastinal disorders | — |
| Pyrexia | General disorders | — |
| Gastroenteritis | Infections and infestations | — |
| Influenza | Infections and infestations | — |
| Ear infection | Infections and infestations | — |
| Sinusitis | Infections and infestations | — |
| Hypersensitivity | Immune system disorders | — |
| Rash | Skin and subcutaneous tissue disorders | — |
| Vomiting | Gastrointestinal disorders | — |
Most-reported serious reactions: Transplant rejection, Bile duct stenosis, Cholangitis, Gastroenteritis, Gastroenteritis viral, Viral infection, Procedural pain, Suicidal ideation.
Data from ClinicalTrials.gov NCT01638559 adverse events section.
The primary objective of this study is to assess the efficacy of immunosuppression withdrawal (ISW) in pediatric liver transplant (tx) recipients.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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