Trial Outcomes & Findings for Safety and Efficacy of IDA for Onchocerciasis (NCT NCT04188301)
NCT ID: NCT04188301
Last Updated: 2024-06-04
Results Overview
Rates of severe adverse events (grade 3 or higher) following 1-day or 3-day triple drug treatment will be compared against those of the comparator regimen of 1 day of IVM/ALB.
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
154 participants
Primary outcome timeframe
Within 7 days following end of treatment
Results posted on
2024-06-04
Participant Flow
Participants recruited in the Nkwanta North District in the Volta Region in Ghana through open community meetings.
Participant milestones
| Measure |
IVM + ALB
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Baseline
STARTED
|
52
|
51
|
51
|
|
Baseline
COMPLETED
|
52
|
51
|
51
|
|
Baseline
NOT COMPLETED
|
0
|
0
|
0
|
|
Month 3
STARTED
|
52
|
51
|
51
|
|
Month 3
COMPLETED
|
52
|
51
|
50
|
|
Month 3
NOT COMPLETED
|
0
|
0
|
1
|
|
Month 12
STARTED
|
52
|
51
|
50
|
|
Month 12
COMPLETED
|
51
|
50
|
48
|
|
Month 12
NOT COMPLETED
|
1
|
1
|
2
|
|
Month 18
STARTED
|
51
|
50
|
48
|
|
Month 18
COMPLETED
|
45
|
50
|
48
|
|
Month 18
NOT COMPLETED
|
6
|
0
|
0
|
Reasons for withdrawal
| Measure |
IVM + ALB
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Month 3
Lost to Follow-up
|
0
|
0
|
1
|
|
Month 12
Lost to Follow-up
|
0
|
0
|
2
|
|
Month 12
Death
|
1
|
1
|
0
|
|
Month 18
Lost to Follow-up
|
6
|
0
|
0
|
Baseline Characteristics
Race and Ethnicity were not collected from any participant.
Baseline characteristics by cohort
| Measure |
IVM + ALB
n=52 Participants
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=51 Participants
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
n=51 Participants
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
Total
n=154 Participants
Total of all reporting groups
|
|---|---|---|---|---|
|
Age, Continuous
|
40.3 years
STANDARD_DEVIATION 12.18 • n=52 Participants
|
38.52 years
STANDARD_DEVIATION 14.08 • n=51 Participants
|
37.65 years
STANDARD_DEVIATION 2.16 • n=51 Participants
|
37.65 years
STANDARD_DEVIATION 13.32 • n=154 Participants
|
|
Sex: Female, Male
Female
|
21 Participants
n=52 Participants
|
18 Participants
n=51 Participants
|
11 Participants
n=51 Participants
|
50 Participants
n=154 Participants
|
|
Sex: Female, Male
Male
|
31 Participants
n=52 Participants
|
33 Participants
n=51 Participants
|
40 Participants
n=51 Participants
|
104 Participants
n=154 Participants
|
|
Race and Ethnicity Not Collected
|
—
|
—
|
—
|
0 Participants
Race and Ethnicity were not collected from any participant.
|
|
Region of Enrollment
Ghana
|
52 participants
n=52 Participants
|
51 participants
n=51 Participants
|
51 participants
n=51 Participants
|
154 participants
n=154 Participants
|
|
Ocular Microfilarae positive
Positive for ocular microfilarae
|
2 Participants
n=52 Participants
|
2 Participants
n=51 Participants
|
0 Participants
n=51 Participants
|
4 Participants
n=154 Participants
|
|
Ocular Microfilarae positive
Negative for ocular microfilarae
|
50 Participants
n=52 Participants
|
49 Participants
n=51 Participants
|
51 Participants
n=51 Participants
|
150 Participants
n=154 Participants
|
PRIMARY outcome
Timeframe: Within 7 days following end of treatmentRates of severe adverse events (grade 3 or higher) following 1-day or 3-day triple drug treatment will be compared against those of the comparator regimen of 1 day of IVM/ALB.
Outcome measures
| Measure |
IVM + ALB
n=52 Participants
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=51 Participants
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
n=51 Participants
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Rates of Severe Adverse Events (SAEs) Across Study Arms
|
0 Participants
|
0 Participants
|
0 Participants
|
PRIMARY outcome
Timeframe: 18 months following treatment.Population: The analysis was conducted on worms from participants who had nodulectomies conducted at 18 months. Not all participants who completed the study had nodulectomies conducted.
The effect of three treatment regimens for killing adult female O. volvulus worms will be compared based on the percentage of all adult female worms in nodules that are alive with embryos in the uterus 18 months after treatment.
Outcome measures
| Measure |
IVM + ALB
n=196 Female worms in nodules
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=274 Female worms in nodules
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
n=300 Female worms in nodules
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Percentage of Worms Killed Across Study Arms
|
127 Female worms in nodules
|
142 Female worms in nodules
|
159 Female worms in nodules
|
PRIMARY outcome
Timeframe: 18 months following treatment.Population: The analysis was conducted on worms from participants who had nodulectomies conducted at 18 months. Not all participants who completed the study had nodulectomies conducted. Female worms were excluded who had collapsed uteri that could not be evaluated for fertility.
The effect of three treatment regimens for sterilizing adult female O. volvulus worms will be compared based on the percentage of all adult female worms that are fertile in the nodules 18 months after treatment.
Outcome measures
| Measure |
IVM + ALB
n=180 Female worms with intact uterus
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=261 Female worms with intact uterus
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
n=281 Female worms with intact uterus
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Percentage of Worms Sterilized Across Study Arms
|
41 Female worms with intact uterus
|
40 Female worms with intact uterus
|
34 Female worms with intact uterus
|
SECONDARY outcome
Timeframe: within 7 days following end of treatmentPopulation: For the Arm IDA x 3 doses, no participants had intraocular microfilariae present at baseline.
Rates of adverse events grade 3 or higher that occur within 7 days of treatment in the subset of participants who have intraocular microfilariae just prior to treatment with IDA will be compared by treatment group.
Outcome measures
| Measure |
IVM + ALB
n=2 Participants
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=2 Participants
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Rates of SAEs by Treatment Group in Those With Intraocular Microfilariae Just Prior to Treatment With IDA
|
0 Participants
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: within 3 months of treatment with IDARates of ocular adverse events of any grade within 3 months will be compared by treatment group.
Outcome measures
| Measure |
IVM + ALB
n=52 Participants
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=51 Participants
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
n=51 Participants
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Rates of Ocular Adverse Events (Any Grade) by Treatment Group
|
4 Participants
|
4 Participants
|
3 Participants
|
SECONDARY outcome
Timeframe: 18 months following treatmentPopulation: Analysis conducted on participants who had nodulectomies conducted at 18 months. Not all participants who completed the study had nodulectomies conducted.
The effectiveness of three treatment regimens for killing adult female O. volvulus worms based on the percentage of all adult female worms in nodules that are alive 18 months after treatment.
Outcome measures
| Measure |
IVM + ALB
n=198 Female worms in nodule
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=274 Female worms in nodule
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
n=300 Female worms in nodule
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Effectiveness of Killing Adult Female Worms
|
127 Female worms in nodule
|
142 Female worms in nodule
|
159 Female worms in nodule
|
SECONDARY outcome
Timeframe: Baseline, 3 months, 12 months, & 18 months following treatment.The effectiveness of three treatment regimens for complete clearance of microfilariae from the skin as determined by skin snips at 3, 12, and 18 months after treatment with IDA will be compared by treatment arm.
Outcome measures
| Measure |
IVM + ALB
n=52 Participants
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=51 Participants
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
n=51 Participants
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Effectiveness of Clearing Microfilariae From Skin by Skin Snips
Baseline
|
3.1 Count of Skin Microfilaria
Interval 1.8 to 5.5
|
1.7 Count of Skin Microfilaria
Interval 0.8 to 3.6
|
NA Count of Skin Microfilaria
Geometric mean could not be estimated because all values were zero
|
|
Effectiveness of Clearing Microfilariae From Skin by Skin Snips
Month 3
|
1.9 Count of Skin Microfilaria
Interval 1.0 to 3.4
|
3 Count of Skin Microfilaria
95% CI could not be estimated because raw data had only one nonzero value
|
2.1 Count of Skin Microfilaria
Interval 0.9 to 4.7
|
|
Effectiveness of Clearing Microfilariae From Skin by Skin Snips
Month 12
|
4.9 Count of Skin Microfilaria
Interval 2.8 to 8.5
|
2.5 Count of Skin Microfilaria
Interval 1.6 to 3.8
|
4.7 Count of Skin Microfilaria
Interval 2.8 to 7.9
|
|
Effectiveness of Clearing Microfilariae From Skin by Skin Snips
Month 18
|
7.0 Count of Skin Microfilaria
Interval 3.6 to 13.9
|
9.0 Count of Skin Microfilaria
Interval 4.6 to 17.6
|
8.6 Count of Skin Microfilaria
Interval 4.3 to 17.1
|
SECONDARY outcome
Timeframe: Baseline, 12 months, and 18 months following treatmentThe effectiveness of three treatment regimens for preventing reappearance of microfilariae in the skin as determined by skin snips at 12 and 18 months after treatment will be compared by treatment arm. Measured by the presence of microfilariae in skin snips.
Outcome measures
| Measure |
IVM + ALB
n=52 Participants
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=51 Participants
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
n=51 Participants
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips
Baseline
|
7 Count of microfilarae+ participants
|
6 Count of microfilarae+ participants
|
0 Count of microfilarae+ participants
|
|
Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips
Month 12
|
23 Count of microfilarae+ participants
|
21 Count of microfilarae+ participants
|
21 Count of microfilarae+ participants
|
|
Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips
Month 18
|
20 Count of microfilarae+ participants
|
15 Count of microfilarae+ participants
|
17 Count of microfilarae+ participants
|
Adverse Events
IVM + ALB
Serious events: 0 serious events
Other events: 11 other events
Deaths: 1 deaths
IDA x 1 Dose
Serious events: 0 serious events
Other events: 15 other events
Deaths: 1 deaths
IDA x 3 Doses
Serious events: 0 serious events
Other events: 11 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
IVM + ALB
n=52 participants at risk
Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
|
IDA x 1 Dose
n=51 participants at risk
Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Single dose of IDA: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
IDA x 3 Doses
n=51 participants at risk
Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Three daily doses of IDA: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
|
|---|---|---|---|
|
General disorders
Chills
|
1.9%
1/52 • Number of events 1 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
5.9%
3/51 • Number of events 3 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
2.0%
1/51 • Number of events 1 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
|
Gastrointestinal disorders
Diarrhea
|
3.8%
2/52 • Number of events 2 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
3.9%
2/51 • Number of events 2 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
3.9%
2/51 • Number of events 2 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
|
Nervous system disorders
Headache
|
1.9%
1/52 • Number of events 1 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
7.8%
4/51 • Number of events 4 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
0.00%
0/51 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
|
Skin and subcutaneous tissue disorders
Itching skin
|
1.9%
1/52 • Number of events 1 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
9.8%
5/51 • Number of events 5 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
7.8%
4/51 • Number of events 4 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
|
Musculoskeletal and connective tissue disorders
Joint or muscle pain
|
5.8%
3/52 • Number of events 3 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
2.0%
1/51 • Number of events 1 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
3.9%
2/51 • Number of events 2 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
|
Eye disorders
Itching, ocular
|
7.7%
4/52 • Number of events 4 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
2.0%
1/51 • Number of events 1 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
3.9%
2/51 • Number of events 2 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
|
General disorders
Waist Pain
|
3.8%
2/52 • Number of events 2 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
2.0%
1/51 • Number of events 1 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
5.9%
3/51 • Number of events 3 • Data was collected on adverse events for safety from baseline to 3 months after treatment. Serious adverse events and mortality were collected throughout the trial from baseline to 18 months after treatment.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place