A Study of Safety, Tolerability and Pharmacokinetics of Apremilast (CC-10004) in Pediatric Subjects With Moderate to Severe Plaque Psoriasis

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02576678
• Collaborator: (none)
• Enrollment: 42
• Locations: 18
• Arm: 1
• Actual Duration (Months): 45.5
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 2, multicenter, open-label study in subjects with moderate to severe plaque psoriasis aged 6 to 17 years, inclusive, intended to assess the safety, tolerability, and PK of apremilast with 2 weeks of oral apremilast treatment followed by a 48-week extension of apremilast treatment. Moderate to severe plaque psoriasis is defined as Psoriasis Area Severity Index (PASI) ≥ 12, Body Surface Area (BSA) ≥ 10%, and static Physician Global Assessment (sPGA) of ≥ 3. The total study duration for each subject will last for up to a total of 107 weeks which includes screening, treatment (including the PK portion of the study and the extension treatment period), two short-term follow-up periods and a long-term follow-up period.

Condition or Disease	Intervention/Treatment	Phase
Psoriasis	Drug: Apremilast	Phase 2

Detailed Description

Each subject will undergo a screening period of up to 5 weeks, a treatment period of 2 weeks with PK sample collection, and an extension treatment period of 48 weeks, to allow subjects access to apremilast treatment if medically appropriate (following the completion of the 2 week PK portion). Regardless of when they stop treatment, subjects should complete two post treatment follow-up visits at approximately 4 and 8 weeks after the last dose. All subjects should complete the final follow-up visit at Week 102 or at a timepoint 52 weeks after the last dose of apremilast was taken in subjects who have withdrawn at any time prior to Week 50. At least 32 subjects will be enrolled into this study to provide an adequate PK profile and safety assessment in subjects of different ages and body weight ranges. Subjects will be divided into 2 age groups (adolescents [ages 12 to 17 years, inclusive] and children [ages 6 to 11 years, inclusive]), with at least 16 subjects in each group. Apremilast treatment will start in older and heavier subjects.

Group 1 (ages 12 to 17 years, inclusive; weight ≥ 35 kg)

• The data collected from the first 8 subjects will be reviewed by an independent data monitoring committee (DMC) to determine if it is appropriate to proceed with dosing the balance of Group 1 subjects and to proceed with dosing in the Group 2 subjects.

and an evaluation of these data by the DMC has been completed.

Group 2 (ages 6 to 11 years, inclusive; weight ≥ 15 kg)

• The dose regimens (dose strength and/or dose frequency) for these first 8 subjects will be based upon the PK and safety assessments from the first 8 subjects in Group 1.

• For the remaining subjects in Group 2, the dose (dose strength and/or dose frequency) will be based upon the subject weight as determined by the PK and safety assessments. The dose strength and/or dose frequency will be adjusted for any safety concerns or for unexpected changes in exposure. In the event of a dose regimen adjustment after the second PK and safety assessment, the first 8 subjects in Group 2 will return to the site for the appropriate dosing adjustment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Open-Label Study to Assess the Safety, Tolerability and Pharmacokinetics of Apremilast (CC-10004) in Pediatric Subjects With Moderate to Severe Plaque Psoriasis
• Actual Study Start Date: Oct 13, 2015
• Actual Primary Completion Date: Sep 4, 2017
• Actual Study Completion Date: Jul 29, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Open label apremilast Apremilast doses of 10-mg, 20-mg or 30-mg tablets have been selected to determine the dose range in adolescents and children with moderate to severe plaque psoriasis. These pediatric dosages are expected to achieve exposures similar to those achieved in adult psoriasis and psoriatic arthritis (PsA) subjects treated with apremilast 30 mg orally twice daily (BID). A staggered, stepwise approach by age range and weight (starting with older and heavier subjects) is considered appropriate for this first-time-in-children study. Doses for younger and lower body weight subjects will be adjusted based on safety and PK data from older and heavier subjects. Subjects will be divided into 2 age groups with at least 16 subjects in each group. Dosing within and between groups will be staggered, based on PK data collected and on a minimum of 2 weeks of safety data.

Drug: Apremilast; Other Names: CC-10004

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [From first dose of apremilast until 28 days after the last dose; up to 29 July 2019; median treatment duration for adolescents apremilast 20 mg and 30 mg was 50.00 and 50.57 weeks respectively and for children was 50.00 weeks.]

   A TEAE is an adverse event with a start date on or after the date of the first dose of apremilast and no later than 28 days after the last dose of apremilast. An adverse event is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. A serious AE is any untoward AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization or in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or constitutes an important medical event. The investigator assessment of severity/intensity of an event was defined as mild, moderate or severe.

2. Maximum Observed Plasma Concentration (Cmax) of Apremilast [For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.]

   Maximum observed plasma concentration (Cmax) of apremilast. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.

3. Time to Maximum Plasma Concentration (Tmax) of Apremilast [For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.]

   Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.

4. Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose of Apremilast (AUC0-12) [For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.]

   Area under the plasma concentration-time curve from time zero to the 12 hours post dose was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.

5. Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration of Apremilast (AUC0-t) [For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.]

   Area under the plasma concentration-time curve from time zero to the last quantifiable time point and was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.

6. Apparent Total Plasma Clearance When Dosed Orally (CL/F) for Apremilast [For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.]

   Apparent total plasma clearance (CL/F) of apremilast was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.

7. Apparent Total Volume of Distribution When Dosed Orally, Based on Study-State (Vss/F) or in the Terminal Phase (Vz/F) [For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.]

   Apparent total volume of distribution when dosed orally, based on study-state (Vss/F) or in the terminal phase (Vz/F). Pharmacokinetic parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.

8. Terminal Phase Elimination Half-Life [For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.]

   Terminal-phase elimination half-life (t ½). PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.

Secondary Outcome Measures

1. Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale [Day 1]

   Taste and acceptability of the apremilast tablet was assessed using a faces Likert Scale on Day 1, initial dosing. The scale consists of options from 1 (dislike very much, illustrated by a frowning face) to 5 (like very much, illustrated by a smiling face).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects must satisfy all of the following criteria to be enrolled in the study:

1. Male or female subjects 6 to 17 years of age, inclusive, at the time the informed consent document is signed by the legal guardian

2. Group 1 Only: ages 12 to 17 years, inclusive, and weighs ≥ 35 kg

3. Group 2 Only: ages 6 to 11 years, inclusive, and weighs ≥ 15 kg

4. Subject is able to swallow the apremilast tablet

5. Able to sign an assent with a legal guardian who can understand and voluntarily sign an informed consent

6. Able to adhere to the study visit schedule and other protocol requirements

7. Must agree to withhold vaccinations during the first 2 weeks of dosing. Inactivated vaccines will be allowed during the extension treatment period

8. Diagnosis of chronic plaque psoriasis for at least 6 months prior to Screening

9. Have moderate to severe plaque psoriasis at Screening and Baseline as defined by:

• Psoriasis Area and Severity Index (PASI) score ≥ 12; and

• Body surface area (BSA) ≥ 10%; and

• Static Physician Global Assessment (sPGA) ≥ 3 (moderate to severe)

1. Disease inadequately controlled by or inappropriate for topical therapy for psoriasis

2. Candidate for systemic or phototherapy

3. Have not been exposed to any or have been exposed to no more than one systemic agent for psoriasis

4. At Screening, laboratory values must be within the following ranges:

• White blood cell (WBC) count Age (yrs) Males (x 103 /µL) Females (x 103 /µL) 6-11 3.5 - 13.65 3.5 - 13.65 12-18 3.5 - 13.15 3.5 - 13.15

• Platelet count Age (yrs) Males (x 103 /µL) Females (x 103 /µL) 6-11 117 - 394 117

• 394 12-18 126 - 400 126 - 400

• Hemoglobin (Hb) Age (yrs) Males (g/dL) Females (g/dL) 6-11 10.0 - 15.5 10.0 - 15.5 12-18 11.0 - 18.1 10.0 - 16.4

1. Male subjects who engage in activity in which conception is possible must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on apremilast and for at least 28 days after the last dose of apremilast

2. All females of childbearing potential (FCBP) must either practice abstinence* from heterosexual contact or use one of the approved contraceptive options as described below while on apremilast and for at least 28 days after dministration of the last dose of apremilast. For the purposes of this study, a female subject is considered of childbearing potential if she is ≥ 12 years old or has reached menarche, whichever occurred first At the time of study entry, and at any time during the study when a female subject of childbearing potential's contraceptive measures or ability to become pregnant changes, the Investigator will educate the subject regarding abstinence or contraception options and the correct and consistent use of effective contraceptive methods in order to successfully prevent pregnancy Females of childbearing potential must have a negative pregnancy test at Screening and Baseline. All FCBP who engage in activity in which conception is possible must use one of the approved contraceptive options described below: Option 1: Any one of the following effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner's vasectomy; OR Option 2: Male or female condom (latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]; PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide * Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

• The presence of any of the following will exclude a subject from enrollment:

1. History of or currently active inflammatory bowel disease

2. Major concurrent medical conditions, pregnancy or lactation

3. Any condition that confounds the ability to interpret data from the study

4. Guttate, erythrodermic, or pustular psoriasis

5. Psoriasis flare or rebound within 4 weeks prior to Screening

6. Evidence of skin conditions that would interfere with clinical assessments

7. History of human immunodeficiency virus infection, or positive result to hepatitis B surface antigen or hepatitis C antibodies at Screening

8. Clinically significant abnormality on 12-Lead ECG at Screening

9. History of active mycobacterial infection with any species (including Mycobacterium tuberculosis) within 3 years of the Screening Visit and without documentation of successful treatment

10. Congenital and acquired immunodeficiencies (eg, Common Variable Immunodeficiency),immunoglobulin A deficiency

11. History of recurrent significant infections

12. Active infection or infection treated with antibiotic treatment within 2 weeks of first dose

13. Any history of or active malignancy

14. History of allergy/intolerance to any component of the investigational product, ie, apremilast, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose 15 cP, titanium dioxide, polydextrose FCC, talc, maltodextrin, medium chain triglycerides, iron oxide red, iron oxide yellow, and iron oxide black.

15. Deficiencies in lactose metabolism, ie, galactose-1-phosphate uridylyltransferase, UDPglactose 4-epimerase, galactokinase or Fanconi Bickel syndrome, including congenital lactase deficiencies, and glucose-galactose malabsorption.

16. Any other significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study or which places the subject at unacceptable risk if he/she were to participate in the study

17. Prior history of suicide attempt at any time in the subject's lifetime prior to screening or enrollment in the study or major psychiatric illness requiring hospitalization within 3 years

18. Answering '"Yes'" to any question on the Columbia-Suicide Severity Rating Scale during screening or at baseline

19. Having received biologic therapy within 5 terminal half-lives, including but not limited to the following time periods:

• Four weeks prior to baseline for etanercept

• Ten weeks prior to baseline for adalimumab

• Twenty-four weeks prior to baseline for ustekinumab

1. Topical therapy within 2 weeks of baseline (including but not limited to topical corticosteroids, topical retinoid or vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin/dithranol)

• Exceptions: low-potency corticosteroids (please refer to the Investigators' Manual) will be allowed as background therapy for treatment of the face, axillae, and groin in accordance with the manufacturers' suggested usage during the course of the study

• Subjects with scalp psoriasis will be permitted to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions

• An unmedicated skin moisturizer (eg, Eucerin®) will be also permitted for body lesions only. Subjects should not use these topical treatments within 24 hours prior to the clinic visit

1. Systemic therapy for psoriasis within 4 weeks prior to baseline (including but not limited to cyclosporine, corticosteroids, methotrexate, oral retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, sulfasalazine, azathioprine, and fumaric acid esters)

2. Use of phototherapy (ie, UVB, PUVA)within 4 weeks prior to baseline

3. Use of any investigational drug within 4 weeks prior to baseline, or 5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer)

4. Children in Care: a child who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation

5. Prior treatment with apremilast

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rady Children's Hospital	San Diego	California	United States	92123
2	Emory University	Atlanta	Georgia	United States	30322
3	Ann & Robert H. Lurie Children's Hospital of Chicago Department of Dermatology	Chicago	Illinois	United States	60611
4	Dundee Dermatology	West Dundee	Illinois	United States	60118
5	Mount Sinai, St. Luke's	New York	New York	United States	10025
6	Texas Dermatology and Laser Specialists	San Antonio	Texas	United States	78218
7	Stollery Children's Hospital	Edmonton	Alberta	Canada	T6G 2B7
8	Nexus Clinical Research	St John's	Newfoundland and Labrador	Canada	A1A 5E8
9	CHU Saint-Justine	Montreal	Quebec	Canada	H3T 1C5
10	Rheinische Friedrich-Wilhelms-Universitaet Bonn - Universitaetsklinikum Bonn	Bonn		Germany	53127
11	Universitatsklinikum Essen	Essen		Germany	45147
12	Universitatsklinikum Klinikum Frankfurt Main	Frankfurt		Germany	60590
13	Kinderkrankenhaus Wilhelmstift, Dermatologie	Hamburg		Germany	22149
14	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany	55131
15	Muenster University Hospital (Universitätsklinikum Muenster)	Munster		Germany	48149
16	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain	08041
17	Hospital Sant Joan de Deu	Esplugues de Llobregat		Spain	08950
18	Hospital La Paz	Madrid		Spain	28046

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Apr 29, 2016
• Statistical Analysis Plan - Mar 15, 2017

More Information

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT02576678
• Other Study ID Numbers: CC-10004-PPSO-001
• First Posted: Oct 15, 2015
• Last Update Posted: May 7, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Amgen: Psoriasis; Moderate to Severe Plaque Psoriasis; Plaque Psoriasis; CC-10004; Apremilast; Pharmacokinetics; Open-label; Safety; Pediatric
• Additional relevant MeSH terms: Psoriasis; Apremilast

Study Results

Participant Flow

Recruitment Details	The study was conducted at 11 study centers in 4 countries, including the United States, Canada, Germany and Spain.
Pre-assignment Detail	Participants were enrolled according to a staggered, stepwise approach by age range and weight starting with older and heavier participants. Dosing within and between groups was staggered based on PK data collected and a minimum of 2 weeks of safety data.

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Period Title: Overall Study
STARTED	13	8	21
Pharmacokinetic (PK) Population	12	8	18
COMPLETED	8	7	16
NOT COMPLETED	5	1	5

Baseline Characteristics

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg	Total
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Total of all reporting groups
Overall Participants	13	8	21	42
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	13.8 (1.77)	14.8 (2.05)	9.3 (1.35)	11.8 (2.95)
Age, Customized (Count of Participants)
6 to 11 years	0 0%	0 0%	21 100%	21 50%
12 to 17 years	13 100%	8 100%	0 0%	21 50%
Sex: Female, Male (Count of Participants)
Female	9 69.2%	1 12.5%	13 61.9%	23 54.8%
Male	4 30.8%	7 87.5%	8 38.1%	19 45.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 7.7%	3 37.5%	5 23.8%	9 21.4%
Not Hispanic or Latino	12 92.3%	5 62.5%	16 76.2%	33 78.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	2 15.4%	0 0%	2 9.5%	4 9.5%
Black or African American	0 0%	0 0%	2 9.5%	2 4.8%
Native Hawaiian or other Pacific Islander	0 0%	1 12.5%	0 0%	1 2.4%
White or Caucasian	10 76.9%	6 75%	16 76.2%	32 76.2%
Other	1 7.7%	1 12.5%	1 4.8%	3 7.1%
Baseline Weight Category (kg) (Count of Participants)
< 15 kg	0 0%	0 0%	0 0%	0 0%
≥ 15 - < 35 kg	0 0%	0 0%	13 61.9%	13 31%
≥ 35 - < 50 kg	3 23.1%	0 0%	4 19%	7 16.7%
≥ 50 - < 70 kg	10 76.9%	0 0%	4 19%	14 33.3%
≥ 70 kg	0 0%	8 100%	0 0%	8 19%
Duration of Plaque Psoriasis (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	7.41 (3.190)	6.96 (4.057)	2.75 (2.057)	4.99 (3.611)
Psoriasis Area Severity Index (PASI) (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	18.78 (11.693)	15.65 (3.430)	18.09 (6.144)	17.84 (7.854)
Baseline Body Mass Index (BMI) category (Count of Participants)
Healthy Weight	7 53.8%	1 12.5%	15 71.4%	23 54.8%
Overweight	2 15.4%	1 12.5%	1 4.8%	4 9.5%
Obesity	4 30.8%	6 75%	5 23.8%	15 35.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	A TEAE is an adverse event with a start date on or after the date of the first dose of apremilast and no later than 28 days after the last dose of apremilast. An adverse event is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. A serious AE is any untoward AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization or in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or constitutes an important medical event. The investigator assessment of severity/intensity of an event was defined as mild, moderate or severe.
Time Frame	From first dose of apremilast until 28 days after the last dose; up to 29 July 2019; median treatment duration for adolescents apremilast 20 mg and 30 mg was 50.00 and 50.57 weeks respectively and for children was 50.00 weeks.

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least 1 dose of apremilast

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Measure Participants	13	8	21
Any TEAE	13 100%	7 87.5%	20 95.2%
Any Drug Related TEAE	11 84.6%	6 75%	17 81%
Any Severe TEAE	1 7.7%	0 0%	1 4.8%
Any Serious TEAE	0 0%	0 0%	1 4.8%
Any Serious Drug-Related TEAE	0 0%	0 0%	0 0%
Any TEAE Leading to Drug Interruption	1 7.7%	0 0%	4 19%
Any TEAE Leading to Drug Withdrawal	0 0%	0 0%	2 9.5%
Any TEAE Leading to Death	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Apremilast
Description	Maximum observed plasma concentration (Cmax) of apremilast. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time Frame	For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.

Outcome Measure Data

Analysis Population Description

The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Measure Participants	12	8	18
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	274.272 (34.3)	410.929 (39.7)	348.146 (47.4)

3. Primary Outcome

Title	Time to Maximum Plasma Concentration (Tmax) of Apremilast
Description	Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time Frame	For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.

Outcome Measure Data

Analysis Population Description

The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Measure Participants	12	8	18
Median (Full Range) [hours]	2.467	3.000	2.000

4. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose of Apremilast (AUC0-12)
Description	Area under the plasma concentration-time curve from time zero to the 12 hours post dose was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time Frame	For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.

Outcome Measure Data

Analysis Population Description

The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Measure Participants	12	8	17
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	1799.717 (36.0)	2901.795 (41.2)	2544.874 (40.8)

5. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration of Apremilast (AUC0-t)
Description	Area under the plasma concentration-time curve from time zero to the last quantifiable time point and was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time Frame	For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.

Outcome Measure Data

Analysis Population Description

The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Measure Participants	12	8	18
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	1794.815 (35.9)	2900.472 (41.4)	2367.641 (50.2)

6. Primary Outcome

Title	Apparent Total Plasma Clearance When Dosed Orally (CL/F) for Apremilast
Description	Apparent total plasma clearance (CL/F) of apremilast was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time Frame	For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.

Outcome Measure Data

Analysis Population Description

The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Measure Participants	12	8	17
Geometric Mean (Geometric Coefficient of Variation) [Liters/hour]	11.113 (36.0)	10.338 (41.2)	7.859 (40.8)

7. Primary Outcome

Title	Apparent Total Volume of Distribution When Dosed Orally, Based on Study-State (Vss/F) or in the Terminal Phase (Vz/F)
Description	Apparent total volume of distribution when dosed orally, based on study-state (Vss/F) or in the terminal phase (Vz/F). Pharmacokinetic parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time Frame	For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.

Outcome Measure Data

Analysis Population Description

The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Measure Participants	12	8	17
Geometric Mean (Geometric Coefficient of Variation) [Liters]	86.870 (56.1)	101.049 (31.6)	55.126 (51.2)

8. Secondary Outcome

Title	Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale
Description	Taste and acceptability of the apremilast tablet was assessed using a faces Likert Scale on Day 1, initial dosing. The scale consists of options from 1 (dislike very much, illustrated by a frowning face) to 5 (like very much, illustrated by a smiling face).
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

The Safety Population consisted of all participants who received at least 1 dose of apremilast.

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Measure Participants	13	8	21
1 (Dislike Very Much)	0 0%	0 0%	3 14.3%
2 (Dislike a Little)	1 7.7%	0 0%	1 4.8%
3 (Not Sure)	5 38.5%	4 50%	3 14.3%
4 (Like a Little)	1 7.7%	1 12.5%	4 19%
5 (Like Very Much)	6 46.2%	3 37.5%	10 47.6%

9. Primary Outcome

Title	Terminal Phase Elimination Half-Life
Description	Terminal-phase elimination half-life (t ½). PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time Frame	For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.

Outcome Measure Data

Analysis Population Description

The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.

Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg	Group 1 Adolescents: Apremilast 30 mg	Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.	Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
Measure Participants	12	8	17
Geometric Mean (Geometric Coefficient of Variation) [hours]	5.418 (43.1)	6.775 (50.3)	4.862 (30.2)

Adverse Events

Time Frame	From first dose of apremilast until 28 days after the last dose; up to 198 weeks; median treatment duration for adolescents apremilast 20 mg and 30 mg was 50.00 and 50.57 weeks respectively and for children was 50.00 weeks.
Arm/Group Title	Group 1 Adolescents: Apremilast 20 mg		Group 1 Adolescents: Apremilast 30 mg		Group 2 Children: Apremilast 20 mg
Arm/Group Description	Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.		Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.		Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
All Cause Mortality
	Group 1 Adolescents: Apremilast 20 mg		Group 1 Adolescents: Apremilast 30 mg		Group 2 Children: Apremilast 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/8 (0%)		0/21 (0%)
Serious Adverse Events
	Group 1 Adolescents: Apremilast 20 mg		Group 1 Adolescents: Apremilast 30 mg		Group 2 Children: Apremilast 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/8 (0%)		1/21 (4.8%)
Nervous system disorders
Syncope	0/13 (0%)		0/8 (0%)		1/21 (4.8%)
Other (Not Including Serious) Adverse Events
	Group 1 Adolescents: Apremilast 20 mg		Group 1 Adolescents: Apremilast 30 mg		Group 2 Children: Apremilast 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		7/8 (87.5%)		19/21 (90.5%)
Ear and labyrinth disorders
Ear pain	0/13 (0%)		1/8 (12.5%)		1/21 (4.8%)
Gastrointestinal disorders
Abdominal distension	1/13 (7.7%)		1/8 (12.5%)		3/21 (14.3%)
Abdominal pain	6/13 (46.2%)		1/8 (12.5%)		11/21 (52.4%)
Abdominal pain upper	2/13 (15.4%)		1/8 (12.5%)		4/21 (19%)
Change of bowel habit	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Constipation	1/13 (7.7%)		0/8 (0%)		1/21 (4.8%)
Diarrhoea	6/13 (46.2%)		4/8 (50%)		5/21 (23.8%)
Dyspepsia	2/13 (15.4%)		1/8 (12.5%)		1/21 (4.8%)
Flatulence	1/13 (7.7%)		0/8 (0%)		1/21 (4.8%)
Gastrointestinal disorder	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Haematemesis	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Nausea	8/13 (61.5%)		4/8 (50%)		10/21 (47.6%)
Vomiting	4/13 (30.8%)		1/8 (12.5%)		8/21 (38.1%)
General disorders
Fatigue	2/13 (15.4%)		0/8 (0%)		0/21 (0%)
Influenza like illness	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Pyrexia	1/13 (7.7%)		1/8 (12.5%)		2/21 (9.5%)
Infections and infestations
Gastroenteritis	2/13 (15.4%)		1/8 (12.5%)		5/21 (23.8%)
Gastroenteritis viral	2/13 (15.4%)		0/8 (0%)		1/21 (4.8%)
Influenza	2/13 (15.4%)		0/8 (0%)		1/21 (4.8%)
Localised infection	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Nasopharyngitis	6/13 (46.2%)		3/8 (37.5%)		7/21 (33.3%)
Pharyngitis streptococcal	1/13 (7.7%)		1/8 (12.5%)		0/21 (0%)
Tonsillitis streptococcal	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Tooth infection	0/13 (0%)		0/8 (0%)		2/21 (9.5%)
Upper respiratory tract infection	0/13 (0%)		0/8 (0%)		2/21 (9.5%)
Urinary tract infection	1/13 (7.7%)		2/8 (25%)		0/21 (0%)
Viral infection	1/13 (7.7%)		1/8 (12.5%)		0/21 (0%)
Injury, poisoning and procedural complications
Dislocation of vertebra	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Ligament sprain	0/13 (0%)		1/8 (12.5%)		0/21 (0%)
Investigations
Blood creatinine increased	0/13 (0%)		1/8 (12.5%)		0/21 (0%)
Blood glucose increased	1/13 (7.7%)		0/8 (0%)		1/21 (4.8%)
Electrocardiogram abnormal	0/13 (0%)		1/8 (12.5%)		0/21 (0%)
Eosinophil count increased	0/13 (0%)		0/8 (0%)		3/21 (14.3%)
Monocyte count increased	0/13 (0%)		0/8 (0%)		2/21 (9.5%)
Protein urine present	1/13 (7.7%)		0/8 (0%)		2/21 (9.5%)
Weight decreased	2/13 (15.4%)		0/8 (0%)		0/21 (0%)
White blood cells urine positive	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/13 (15.4%)		1/8 (12.5%)		1/21 (4.8%)
Obesity	0/13 (0%)		1/8 (12.5%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/13 (7.7%)		0/8 (0%)		2/21 (9.5%)
Foot deformity	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Joint swelling	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Musculoskeletal pain	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Pain in extremity	2/13 (15.4%)		0/8 (0%)		0/21 (0%)
Patellofemoral pain syndrome	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Nervous system disorders
Dizziness	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Headache	7/13 (53.8%)		1/8 (12.5%)		11/21 (52.4%)
Syncope	0/13 (0%)		1/8 (12.5%)		1/21 (4.8%)
Psychiatric disorders
Anxiety	1/13 (7.7%)		0/8 (0%)		1/21 (4.8%)
Attention deficit/hyperactivity disorder	0/13 (0%)		1/8 (12.5%)		0/21 (0%)
Depressed mood	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Insomnia	2/13 (15.4%)		0/8 (0%)		1/21 (4.8%)
Intentional self-injury	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Mood swings	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	2/13 (15.4%)		0/8 (0%)		1/21 (4.8%)
Respiratory, thoracic and mediastinal disorders
Asthma exercise induced	1/13 (7.7%)		0/8 (0%)		0/21 (0%)
Cough	3/13 (23.1%)		1/8 (12.5%)		2/21 (9.5%)
Nasal congestion	1/13 (7.7%)		0/8 (0%)		1/21 (4.8%)
Oropharyngeal pain	2/13 (15.4%)		0/8 (0%)		3/21 (14.3%)
Skin and subcutaneous tissue disorders
Acne	1/13 (7.7%)		0/8 (0%)		0/21 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results from a center cannot be submitted for publication before results of multicenter study are published unless it is > 1 year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 additional days. Investigator must delete confidential information before submission and defer publication to permit patent applications.