Trial Outcomes & Findings for PTH(1-34) and Pelvic Fracture Healing - a Randomized Controlled Trial (NCT NCT02972424)
NCT ID: NCT02972424
Last Updated: 2022-07-27
Results Overview
Evidence of cortical bridging based on Focus CT,
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
35 participants
Primary outcome timeframe
3 months
Results posted on
2022-07-27
Participant Flow
We included men and postmenopausal women \>50 years of age within 1 month of acute pelvic fractures, occurring with minimal trauma. Sites included Hospital for Special Surgery, Helen Hayes Hospital or New York Presbyterian Hospital. Patients who had one or multiple pubic rami fractures (with or without sacral fractures) were included in the study. The first person was recruited into the study in May 2017 and the last person was recruited in August 2019.
Participants were excluded if they were unable to provide informed consent, if they were non-ambulatory prior to the fracture, or if they had a contraindication or intolerance to teriparatide. Serum calcium level had to be within normal range, serum creatinine could not be elevated more than 1.5 times above upper normal limit for age and alkaline phosphatase levels could not be greater than 1.5 times the upper normal limit.
Participant milestones
| Measure |
Teriparatide
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
Placebo
Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Placebo: Matching placebo as a prefilled syringe with all inactive ingredients
|
|---|---|---|
|
3 Month Endpoints- Blinded Portion
STARTED
|
18
|
17
|
|
3 Month Endpoints- Blinded Portion
COMPLETED
|
17
|
12
|
|
3 Month Endpoints- Blinded Portion
NOT COMPLETED
|
1
|
5
|
|
Open Label Extension 3 to 12 Months
STARTED
|
17
|
12
|
|
Open Label Extension 3 to 12 Months
COMPLETED
|
12
|
9
|
|
Open Label Extension 3 to 12 Months
NOT COMPLETED
|
5
|
3
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
PTH(1-34) and Pelvic Fracture Healing - a Randomized Controlled Trial
Baseline characteristics by cohort
| Measure |
Teriparatide
n=18 Participants
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
Placebo
n=15 Participants
Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Placebo: Matching placebo as a prefilled syringe with all inactive ingredients
|
Total
n=33 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
81.6 years
STANDARD_DEVIATION 8.1 • n=5 Participants
|
81.0 years
STANDARD_DEVIATION 11.5 • n=7 Participants
|
81.4 years
STANDARD_DEVIATION 9.7 • n=5 Participants
|
|
Sex: Female, Male
Female
|
16 Participants
n=5 Participants
|
12 Participants
n=7 Participants
|
28 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
2 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
5 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
18 Participants
n=5 Participants
|
15 Participants
n=7 Participants
|
33 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
17 Participants
n=5 Participants
|
15 Participants
n=7 Participants
|
32 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
18 participants
n=5 Participants
|
15 participants
n=7 Participants
|
33 participants
n=5 Participants
|
|
Body mass index (kg/m^2)
|
22.1 kg/m^2
STANDARD_DEVIATION 3.5 • n=5 Participants
|
22.5 kg/m^2
STANDARD_DEVIATION 5.5 • n=7 Participants
|
22.3 kg/m^2
STANDARD_DEVIATION 4.4 • n=5 Participants
|
|
history of fracture
|
12 Participants
n=5 Participants
|
12 Participants
n=7 Participants
|
24 Participants
n=5 Participants
|
|
multiple rami fractures
|
18 Participants
n=5 Participants
|
14 Participants
n=7 Participants
|
32 Participants
n=5 Participants
|
|
displaced fractures
|
8 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
17 Participants
n=5 Participants
|
|
sacral fractures
|
7 Participants
n=5 Participants
|
6 Participants
n=7 Participants
|
13 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 3 monthsEvidence of cortical bridging based on Focus CT,
Outcome measures
| Measure |
Teriparatide
n=18 Participants
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
Placebo
n=15 Participants
Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Placebo: Matching placebo as a prefilled syringe with all inactive ingredients
|
|---|---|---|
|
Number of Participants With Evidence of Cortical Bridging for Fracture Healing
|
9 Participants
|
8 Participants
|
SECONDARY outcome
Timeframe: 3 monthsPopulation: participants with a 3 month visit
Leads to a faster reduction in pain as assessed by the Numeric Rating Scale of 0 (no pain) to 10 (worst pain). The mean reduction in pain score from 0 to 3 months is reported. Higher scores mean a greater reduction in pain.
Outcome measures
| Measure |
Teriparatide
n=17 Participants
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
Placebo
n=12 Participants
Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Placebo: Matching placebo as a prefilled syringe with all inactive ingredients
|
|---|---|---|
|
Change in Pain by Numeric Rating Scale Between Baseline and Three Months
|
1.94 score on a scale
Standard Deviation 3.42
|
2.78 score on a scale
Standard Deviation 3.14
|
SECONDARY outcome
Timeframe: 3 monthsPopulation: All persons completing 3 month visit to provide data.
More rapidly improved functional outcome using a short physical performance battery to assess lower extremity function (walking speed, repeated chair stands, and balance) at 3 months. Scale is 0 to 100 with higher scores indicating better physical performance.
Outcome measures
| Measure |
Teriparatide
n=17 Participants
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
Placebo
n=12 Participants
Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Placebo: Matching placebo as a prefilled syringe with all inactive ingredients
|
|---|---|---|
|
Functional Outcome Using a Battery That Includes Walking Speed, Repeated Chair Stands, and Balance at 3 Months
|
74.2 score on a scale
Standard Error 3.6
|
59.9 score on a scale
Standard Error 4.7
|
SECONDARY outcome
Timeframe: 12 monthsPopulation: Participants providing 12 month data and taking study drug during extension
More rapidly improved functional outcome using a short physical performance battery to assess lower extremity function (walking speed, repeated chair stands, and balance) at 12 months. Scale is 0 to 100 with higher scores indicating better performance.
Outcome measures
| Measure |
Teriparatide
n=10 Participants
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
Placebo
n=7 Participants
Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Placebo: Matching placebo as a prefilled syringe with all inactive ingredients
|
|---|---|---|
|
Physical Function at 12 Months Using a Battery That Includes Walking Speed, Repeated Chair Stands, and Balance
|
70.0 score on a scale 0-100
Standard Error 3.3
|
64.9 score on a scale 0-100
Standard Error 4.1
|
SECONDARY outcome
Timeframe: 12 monthsPopulation: Participants who completed 12 month visit
Pain at 12 months as assessed by the Numeric Rating Scale (0 to 10 where 0 means no pain and 10 worst pain)
Outcome measures
| Measure |
Teriparatide
n=12 Participants
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
Placebo
n=9 Participants
Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Placebo: Matching placebo as a prefilled syringe with all inactive ingredients
|
|---|---|---|
|
Pain at 12 Months Based on the Numeric Rating Scale
|
1.5 score on a scale
Standard Error 0.4
|
1.9 score on a scale
Standard Error 0.6
|
Adverse Events
Teriparatide for 3 Months Then Open Label for 9 Months
Serious events: 4 serious events
Other events: 12 other events
Deaths: 1 deaths
Placebo for 3 Months
Serious events: 1 serious events
Other events: 4 other events
Deaths: 0 deaths
Open Label Teriparatide Following Placebo
Serious events: 3 serious events
Other events: 7 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Teriparatide for 3 Months Then Open Label for 9 Months
n=18 participants at risk
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
Placebo for 3 Months
n=17 participants at risk
Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Placebo: Matching placebo as a prefilled syringe with all inactive ingredients
|
Open Label Teriparatide Following Placebo
n=12 participants at risk
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
|---|---|---|---|
|
Cardiac disorders
cardiac
|
11.1%
2/18 • Number of events 2 • One year
|
0.00%
0/17 • One year
|
8.3%
1/12 • Number of events 1 • One year
|
|
Musculoskeletal and connective tissue disorders
orthopedic procedure
|
0.00%
0/18 • One year
|
0.00%
0/17 • One year
|
25.0%
3/12 • Number of events 3 • One year
|
|
Gastrointestinal disorders
dysphagia
|
0.00%
0/18 • One year
|
5.9%
1/17 • Number of events 1 • One year
|
0.00%
0/12 • One year
|
|
Gastrointestinal disorders
ulcer
|
5.6%
1/18 • Number of events 1 • One year
|
0.00%
0/17 • One year
|
0.00%
0/12 • One year
|
|
Blood and lymphatic system disorders
hyponatremia
|
5.6%
1/18 • Number of events 1 • One year
|
0.00%
0/17 • One year
|
0.00%
0/12 • One year
|
Other adverse events
| Measure |
Teriparatide for 3 Months Then Open Label for 9 Months
n=18 participants at risk
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
Placebo for 3 Months
n=17 participants at risk
Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Placebo: Matching placebo as a prefilled syringe with all inactive ingredients
|
Open Label Teriparatide Following Placebo
n=12 participants at risk
TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Teriparatide Prefilled Syringe: TPTD 20 mcg
|
|---|---|---|---|
|
Respiratory, thoracic and mediastinal disorders
Upper respiratory
|
11.1%
2/18 • Number of events 2 • One year
|
0.00%
0/17 • One year
|
8.3%
1/12 • Number of events 1 • One year
|
|
Gastrointestinal disorders
nausea vomiting diarrhea
|
22.2%
4/18 • Number of events 4 • One year
|
11.8%
2/17 • Number of events 2 • One year
|
8.3%
1/12 • Number of events 1 • One year
|
|
Infections and infestations
UTI
|
22.2%
4/18 • Number of events 4 • One year
|
0.00%
0/17 • One year
|
16.7%
2/12 • Number of events 2 • One year
|
|
Musculoskeletal and connective tissue disorders
muscle or joint pain
|
50.0%
9/18 • Number of events 9 • One year
|
5.9%
1/17 • Number of events 1 • One year
|
16.7%
2/12 • Number of events 2 • One year
|
|
Social circumstances
fatigue, loss of apatite, lethargy
|
16.7%
3/18 • Number of events 3 • One year
|
0.00%
0/17 • One year
|
0.00%
0/12 • One year
|
|
Musculoskeletal and connective tissue disorders
Fracture
|
11.1%
2/18 • Number of events 2 • One year
|
5.9%
1/17 • Number of events 1 • One year
|
8.3%
1/12 • Number of events 1 • One year
|
|
Skin and subcutaneous tissue disorders
bruising, blotching, squamous cell excision
|
5.6%
1/18 • Number of events 2 • One year
|
0.00%
0/17 • One year
|
8.3%
1/12 • Number of events 1 • One year
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place