Trial Outcomes & Findings for Evaluating the Safety and Effectiveness of Bone Marrow Transplants in Children With Sickle Cell Disease (BMT CTN 0601) (NCT NCT00745420)

NCT ID: NCT00745420

Last Updated: 2022-12-09

Results Overview

EFS is defined as percentage of participants that have not had an event. Primary or secondary graft rejection, disease recurrence, or death will count as events for this endpoint.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 30 participants
• Primary outcome timeframe: 2 years
• Results posted on: 2022-12-09

Participant Flow

Participants were enrolled between August 2008 and April 2014 from 19 different transplant centers.

Participant milestones

Measure	Hematopoietic Stem Cell Transplantation Bone Marrow Transplant with GVHD Prophylaxis Regimen
Overall Study STARTED	30
Overall Study COMPLETED	29
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure	Hematopoietic Stem Cell Transplantation Bone Marrow Transplant with GVHD Prophylaxis Regimen
Overall Study Ineligible	1

Baseline Characteristics

Evaluating the Safety and Effectiveness of Bone Marrow Transplants in Children With Sickle Cell Disease (BMT CTN 0601)

Baseline characteristics by cohort

Measure	Hematopoietic Stem Cell Transplantation n=29 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Age, Continuous	14 years n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants
Sex: Female, Male Male	16 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	26 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	3 Participants n=5 Participants
Indications for Transplant Stroke	12 Participants n=5 Participants
Indications for Transplant Trans cranial doppler velocity > 200cm/s	2 Participants n=5 Participants
Indications for Transplant Acute chest syndrome	4 Participants n=5 Participants
Indications for Transplant Vaso-occlusive pain crisis	12 Participants n=5 Participants
Chronic Blood Transfusion Prior to Transplant	14 Participants n=5 Participants
Karnofsky Performance Score 100	17 Participants n=5 Participants
Karnofsky Performance Score 90	9 Participants n=5 Participants
Karnofsky Performance Score 80	2 Participants n=5 Participants
Karnofsky Performance Score 70	1 Participants n=5 Participants
Cytomegalovirus (CMV) Status CMV - donor and recipient	8 Participants n=5 Participants
Cytomegalovirus (CMV) Status CMV + donor and recipient	9 Participants n=5 Participants
Cytomegalovirus (CMV) Status CMV - donor and CMV + recipient	3 Participants n=5 Participants
Cytomegalovirus (CMV) Status CMV + donor and CMV - recipient	9 Participants n=5 Participants
Donor Blood Type Match ABO Blood group matched	15 Participants n=5 Participants
Donor Blood Type Match ABO Blood group major mismatch	9 Participants n=5 Participants
Donor Blood Type Match ABO Blood group minor mismatch	5 Participants n=5 Participants
Donor Gender Match Gender matched transplants	15 Participants n=5 Participants
Donor Gender Match Female donor, male recipient	7 Participants n=5 Participants
Donor Gender Match Male donor, female recipient	7 Participants n=5 Participants
Donor Age	35 years n=5 Participants
Donor Race/Ethnicity Caucasian	11 Participants n=5 Participants
Donor Race/Ethnicity Black or African American	11 Participants n=5 Participants
Donor Race/Ethnicity Multiracial	5 Participants n=5 Participants
Donor Race/Ethnicity Not Reported	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: 2 years

EFS is defined as percentage of participants that have not had an event. Primary or secondary graft rejection, disease recurrence, or death will count as events for this endpoint.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=29 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Percentage of Participants With Event-Free Survival (EFS) 1 year	76 percentage of participants Interval 56.0 to 88.0
Percentage of Participants With Event-Free Survival (EFS) 2 years	69 percentage of participants Interval 48.0 to 82.0

SECONDARY outcome

Timeframe: 2 years

OS is defined as the percentage of participants that have not died.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=29 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Percentage of Participants With Overall Survival (OS) 1 year	86 percentage of participants Interval 67.0 to 95.0
Percentage of Participants With Overall Survival (OS) 2 years	79 percentage of participants Interval 59.0 to 90.0

SECONDARY outcome

Timeframe: Up to 100 days

Time to neutrophil recovery is defined as the time of the first of three measurements on consecutive days where the patient has an absolute neutrophil count of >= 500/uL following conditioning regimen induced nadir. Time to platelet recovery is defined as the time of the first of three measurements on consecutive days where the patient has achieved a platelet count > 50,000/uL and is platelet transfusion independent for a minimum of seven days following conditioning regimen induced nadir.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=29 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Neutrophil and Platelet Recovery Neutrophil Recovery	12 days Interval 6.0 to 16.0
Neutrophil and Platelet Recovery Platelet Recovery	24 days Interval 7.0 to 90.0

SECONDARY outcome

Timeframe: 1 year

Primary graft rejection is defined as the presence of less than 20% donor cells as assessed by peripheral blood or bone marrow chimerism assays on or after Day 42. Secondary graft rejection is defined as the presence of less than 20% donor derived hematopoietic cells in peripheral blood or bone marrow that occurs after prior evidence of 20% or greater donor cells.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=29 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Graft Rejection Primary Graft Rejection	2 Participants
Graft Rejection Secondary Graft Rejection	1 Participants

SECONDARY outcome

Timeframe: 100 days

Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995:

Skin stage:

0: No rash

1. Rash <25% of body surface area

2. Rash on 25-50% of body surface area

3. Rash on > 50% of body surface area

4. Generalized erythroderma with bullous formation

Liver stage (based on bilirubin level)*:

0: <2 mg/dL

1. 2-3 mg/dL

2. 3.01-6 mg/dL

3. 6.01-15.0 mg/dL

4. >15 mg/dL

GI stage*:

0: No diarrhea or diarrhea <500 mL/day

1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD

2. Diarrhea 1000-1499 mL/day

3. Diarrhea >1500 mL/day

4. Severe abdominal pain with or without ileus * If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.

GVHD grade:

0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=29 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Percentage of Participants With Acute Graft-vs-Host-Disease (GVHD) Grade II-IV Acute GVHD	28 percentage of participants Interval 13.0 to 45.0
Percentage of Participants With Acute Graft-vs-Host-Disease (GVHD) Grade III-IV Acute GVHD	17 percentage of participants Interval 6.0 to 33.0

SECONDARY outcome

Timeframe: 1 year post-transplant

Chronic GVHD is defined per NIH 2005 Consensus Criteria.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=29 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Percentage of Participants With Chronic GVHD	62 percentage of participants Interval 41.0 to 77.0

SECONDARY outcome

Timeframe: 1 year post-transplant

Chronic GVHD severity is defined per NIH 2005 Consensus Criteria.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=29 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Number of Participants With Chronic GVHD by Severity None	10 Participants
Number of Participants With Chronic GVHD by Severity Mild	6 Participants
Number of Participants With Chronic GVHD by Severity Moderate	8 Participants
Number of Participants With Chronic GVHD by Severity Severe	5 Participants

SECONDARY outcome

Timeframe: 1 year

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=29 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Percentage of Participants With Posterior Reversible Encephalopathy Syndrome (PRES)	34 percentage of participants Interval 18.0 to 52.0

SECONDARY outcome

Timeframe: 100 days post-transplant

Population: Participants age 10 years or older that returned the HRQL surveys

HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in participant reported scores on these HRQL subscales from a pre-transplant baseline assessment to day 100 post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=18 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Change From Baseline to Day 100 in Participant Reported Health-Related Quality of Life (HRQL) Self esteem score	-0.59 units on a scale Standard Error 4.51
Change From Baseline to Day 100 in Participant Reported Health-Related Quality of Life (HRQL) General health perception score	-1.90 units on a scale Standard Error 4.29
Change From Baseline to Day 100 in Participant Reported Health-Related Quality of Life (HRQL) Change in health score	0.33 units on a scale Standard Error 0.45

SECONDARY outcome

Timeframe: 100 days post-transplant

Population: Parent proxies of participants that returned the HRQL surveys

HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in parent proxy reported scores on these HRQL subscales from a pre-transplant baseline assessment to day 100 post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=21 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Change From Baseline to Day 100 in Parent Proxy Reported Health-Related Quality of Life (HRQL) Self esteem scale score	-15.12 units on a scale Standard Error 4.89
Change From Baseline to Day 100 in Parent Proxy Reported Health-Related Quality of Life (HRQL) General health perception score	11.13 units on a scale Standard Error 2.51
Change From Baseline to Day 100 in Parent Proxy Reported Health-Related Quality of Life (HRQL) Change in health score	0.90 units on a scale Standard Error 0.38

SECONDARY outcome

Timeframe: 180 days post-transplant

Population: Participants age 10 years or older that returned the HRQL surveys

HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in participant reported scores on these HRQL subscales from a pre-transplant baseline assessment to day 180 post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=16 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Change From Baseline to Day 180 in Participant Reported Health-Related Quality of Life (HRQL) Self esteem scale score	-4.33 units on a scale Standard Error 5.87
Change From Baseline to Day 180 in Participant Reported Health-Related Quality of Life (HRQL) General health perception score	-6.69 units on a scale Standard Error 4.99
Change From Baseline to Day 180 in Participant Reported Health-Related Quality of Life (HRQL) Change in health score	0.19 units on a scale Standard Error 0.52

SECONDARY outcome

Timeframe: 180 days post-transplant

Population: Parent proxies of participants that returned the HRQL surveys

HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in parent proxy reported scores on these HRQL subscales from a pre-transplant baseline assessment to day 180 post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=20 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Change From Baseline to Day 180 in Parent Proxy Reported Health-Related Quality of Life (HRQL) Self esteem scale score	-11.46 units on a scale Standard Error 6.28
Change From Baseline to Day 180 in Parent Proxy Reported Health-Related Quality of Life (HRQL) General health perception score	7.63 units on a scale Standard Error 3.31
Change From Baseline to Day 180 in Parent Proxy Reported Health-Related Quality of Life (HRQL) Change in health score	1.15 units on a scale Standard Error 0.36

SECONDARY outcome

Timeframe: 1 year post-transplant

Population: Participants age 10 years or older that returned the HRQL surveys

HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in participant reported scores on these HRQL subscales from a pre-transplant baseline assessment to 1 year post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=13 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Change From Baseline to 1 Year in Participant Reported Health-Related Quality of Life (HRQL) Self esteem scale score	4.97 units on a scale Standard Error 5.33
Change From Baseline to 1 Year in Participant Reported Health-Related Quality of Life (HRQL) General health perception score	6.99 units on a scale Standard Error 6.35
Change From Baseline to 1 Year in Participant Reported Health-Related Quality of Life (HRQL) Change in health score	1.46 units on a scale Standard Error 0.35

SECONDARY outcome

Timeframe: 1 year post-transplant

Population: Parent proxies of participants that returned the HRQL surveys

HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in parent proxy reported scores on these HRQL subscales from a pre-transplant baseline assessment to 1 year post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.

Outcome measures

Measure	Hematopoietic Stem Cell Transplantation n=15 Participants Bone Marrow Transplant with GVHD Prophylaxis Regimen
Change From Baseline to 1 Year in Parent Proxy Reported Health-Related Quality of Life (HRQL) Self esteem scale score	-3.61 units on a scale Standard Error 6.66
Change From Baseline to 1 Year in Parent Proxy Reported Health-Related Quality of Life (HRQL) General health perception score	8.89 units on a scale Standard Error 5.27
Change From Baseline to 1 Year in Parent Proxy Reported Health-Related Quality of Life (HRQL) Change in health score	1.53 units on a scale Standard Error 0.48

Adverse Events

Hematopoietic Stem Cell Transplantation

Serious events: 21 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Measure	Hematopoietic Stem Cell Transplantation n=29 participants at risk Bone Marrow Transplant with GVHD Prophylaxis Regimen
Blood and lymphatic system disorders Autoimmune haemolytic anaemia	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Cardiac disorders Cardiac arrest	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Gastrointestinal disorders Pancreatitis	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
General disorders Death	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Infections and infestations Sepsis	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Infections and infestations Septic shock	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Infections and infestations Staphylococcal sepsis	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Investigations Oxygen saturation decreased	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Nervous system disorders Cerebrovascular accident	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Nervous system disorders Depressed level of consciousness	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Nervous system disorders Posterior reversible encephalopathy syndrome	6.9% 2/29 • Number of events 2 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Nervous system disorders Seizure	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Nervous system disorders Somnolence	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Psychiatric disorders Mental status changes	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Renal and urinary disorders Acute kidney injury	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Respiratory, thoracic and mediastinal disorders Respiratory failure	6.9% 2/29 • Number of events 2 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Skin and subcutaneous tissue disorders Rash macular	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Surgical and medical procedures Cholecystectomy	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.

Other adverse events

Measure	Hematopoietic Stem Cell Transplantation n=29 participants at risk Bone Marrow Transplant with GVHD Prophylaxis Regimen
Nervous system disorders Seizure	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Respiratory, thoracic and mediastinal disorders Respiratory failure	3.4% 1/29 • Number of events 1 • 2 years post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.

Additional Information

Adam Mendizabal, PhD

The Emmes Corporation

Phone: 301-251-1161

Email: amendizabal@emmes.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place