Safety, Tolerability, and Efficacy Study of rAvPAL-PEG Administered Daily in Subjects With Phenylketonuria (PKU)

• Sponsor: BioMarin Pharmaceutical (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01212744
• Collaborator: (none)
• Enrollment: 16
• Locations: 9
• Arm: 1
• Duration (Months): 49
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of daily administration of rAvPAL-PEG on the reduction of blood Phe concentrations in subjects with PKU.

Condition or Disease	Intervention/Treatment	Phase
Phenylketonuria	Drug: rAvPAL-PEG	Phase 2

Detailed Description

This 16-week multi-center, open-label, Phase 2 study is designed to evaluate the safety, tolerability,and efficacy of daily SC injections of rAvPAL-PEG in subjects with PKU. Subjects who are naïve to prior treatment with rAvPAL-PEG and who have met the other study eligibility criteria will be enrolled at approximately 8 sites in the US and Canada. Up to 6 daily dose levels of rAvPAL-PEG are planned and may be assessed during this study (0.06 mg/kg/day, 0.1 mg/kg/day, 0.2 mg/kg/day;0.4 mg/kg/day, 0.6 mg/kg/day, or 0.8 mg/kg/day). Enrollment will begin with the 0.4 mg/kg/day dose level and additional higher or lower doses may be added. The additional dose levels chosen for assessment will be based on the safety (systemic reaction or clinically significant abnormal laboratory test results assessed as related to study drug) and efficacy (blood Phe reduction to less than or equal to 60 μmol/L) information of at least 3 subjects with at least 2 weeks of daily dosing with rAvPAL-PEG. Initiation of dosing at higher or lower dose levels will be per the determination of the Sponsor's Medical Officer in consultation with the Investigator.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-Label Study to Evaluate the Safety, Tolerability, and Efficacy of Subcutaneous Dose Levels of rAvPAL-PEG Administered Daily in Subjects With Phenylketonuria
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rAvPAL-PEG rAvPAL-PEG in varying doses	Drug: rAvPAL-PEG; 0.06 mg/kg/day, 0.1 mg/kg/day, 0.2 mg/kg/day, 0.4 mg/kg/day, 0.6 mg/kg/day, 0.8 mg/kg/day; Other Names: Recombinant Anabaena variabilis phenylalanine ammonia lyase

Outcome Measures

Primary Outcome Measures

1. Blood Phenylalanine Concentration [Baseline, Week 16]

   Plasma Phe

Secondary Outcome Measures

1. Study Drug Related Adverse Events [Weekly]

   Safety will be evaluated on the incidence of AEs and clinically significant changes in vital signs as well as clinical labs and ECG. Please refer to AE section below for comprehensive listing of all adverse events recorded during study.

2. Percentage of Participants With PAL IgG Antibody Percentage of Participants With Positive PAL IgG [Baseline, Week 16]

   Antibody against phenylalanine ammonia lyase (PAL)

3. Plasma Concentrations of rAvPAL-PEG (BMN 165) [Baseline, Week 8, Week 13]

   Measurements taken pre-dose

4. Percentage of Participants With PEG-IgG Antibody Positivity [Baseline, Week 16]

   Antibodies against polyethylene glycol (PEG) of the IgG isotype

5. Percentage of Participants With PAL-IgM Antibody Positivity [Baseline, Week 16]

   Antibodies against phenylalanine ammonia lyase (PAL) of the IgM isotype

6. Percentage of Participants With PEG-IgM Antibody Positivity [Baseline, Week 16]

   Antibodies against polyethylene glycol (PEG) of the IgM isotype

7. Percentage of Participants With Neutralizing Antibody Positivity [Baseline, Week 16]

   Antibody positivity over time

8. Percentage of Participants With PAL-IgE Antibody Positivity [Baseline, Week 16]

   Antibodies against phenylalanine ammonia lyase (PAL) of the IgE isotype

9. Percentage of Participants With PAL-PEG-IgE Antibody Positivity [Baseline, Week 16]

   Antibodies against phenylalanine ammonia lyase (PAL)-polyethylene glycol (PEG) of the IgE isotype

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of PKU with both of the following: current blood Phe concentration of ≥ 600 micromol/L at screening and average blood Phe concentration of ≥ 600 micromol/L over the past 3 years, using available data

• Evidence that the subject is a non-responder to Kuvan® treatment (ie, 4 weeks of treatment with 20 mg/kg/day of Kuvan, insufficient response per investigator determination, and treatment end date ≥ 14 days prior to Day 1 [ie, first dose]). Subjects who have had a previous response to Kuvan® treatment but are not currently taking Kuvan® because of noncompliance and have been off treatment for ≥ 4 months prior to screening are eligible for participation.

• Willing and able to provide written, signed informed consent, or, in the case of participants under the age of 18, provide written assent (if required) and written informed consent by a legally authorized representative, after the nature of the study has been explained, and prior to any research-related procedures.

• Willing and able to comply with all study procedures.

• Between the ages of 16 and 70 years, inclusive.

• Negative pregnancy test at screening and willing to have additional pregnancy tests performed during the study for females of childbearing potential only. Females considered not of childbearing potential are those who have been in menopause for at least 2 years or have had a tubal ligation at least 1 year prior to screening, or who have had a total hysterectomy.

• Willing to use an acceptable method of contraception while participating in the study (sexually active subjects only).

• Maintained a stable diet with no significant modifications during the 4 weeks preceding the administration of study drug.

• In generally good health as evidenced by physical examination, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and ECG at screening.

Exclusion Criteria:

• Prior use of rAvPAL-PEG.

• Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.

• Use of any medication that is intended to treat PKU within 14 days prior to the administration of study drug.

• Use or planned use of any injectable drugs containing PEG (other than rAvPAL-PEG), including Depo-Provera, within 3 months prior to screening and during study participation.

• Known hypersensitivity to rAvPAL-PEG excipients.

• Breastfeeding at screening or planning to become pregnant (self or partner) or to breastfeed at any time during the study.

• Concurrent disease or condition that would interfere with study participation or safety (eg, history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurological, oncologic, or psychiatric disease).

• Any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study.

• Alanine aminotransferase (ALT) concentration > 2 times the upper limit of normal.

• Creatinine > 1.5 times the upper limit of normal.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Children's Hospital	Aurora	Colorado	United States	80045
2	University of Florida	Gainesville	Florida	United States	32610
3	Weisskopf Child Evaluation Center / University of Louisville	Louisville	Kentucky	United States	40202
4	University of Missouri	Columbia	Missouri	United States	65212
5	Washington University Center for Applied Research Sciences	Saint Louis	Missouri	United States	63110
6	Albany Medical Center	Albany	New York	United States	12208
7	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
8	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
9	University of Wisconsin-Madison	Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• BioMarin Pharmaceutical

Investigators

• Study Director: Ari Gershman, MD, BioMarin Pharmaceutical

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: BioMarin Pharmaceutical
• ClinicalTrials.gov Identifier: NCT01212744
• Other Study ID Numbers: PAL-004
• First Posted: Oct 1, 2010
• Last Update Posted: Feb 26, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by BioMarin Pharmaceutical: PEG PAL; PKU; injection;
• Additional relevant MeSH terms: Phenylketonurias

Study Results

Participant Flow

Arm/Group Title	rAvPAL-PEG
Arm/Group Description	rAvPAL-PEG in varying doses rAvPAL-PEG: 0.06 mg/kg/day, 0.1 mg/kg/day, 0.2 mg/kg/day, 0.4 mg/kg/day, 0.6 mg/kg/day, 0.8 mg/kg/day
Period Title: Overall Study
STARTED	16
COMPLETED	15
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	rAvPAL-PEG
Arm/Group Description	rAvPAL-PEG in varying doses
Overall Participants	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.2 (8.27)
Age, Customized (Count of Participants)
< 18 years of age	0 0%
> or = 18 years of age	16 100%
Sex: Female, Male (Count of Participants)
Female	13 81.3%
Male	3 18.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	16 100%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	16 100%
Other	0 0%

Outcome Measures

1. Primary Outcome

Title	Blood Phenylalanine Concentration
Description	Plasma Phe
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

The efficacy population will consist of all subjects who received any amount of study drug and have post-treatment blood Phe concentration measurements.

Arm/Group Title	rAvPAL-PEG
Arm/Group Description	rAvPAL-PEG in varying doses rAvPAL-PEG: 0.06 mg/kg/day, 0.1 mg/kg/day, 0.2 mg/kg/day, 0.4 mg/kg/day, 0.6 mg/kg/day, 0.8 mg/kg/day
Measure Participants	16
Baseline	1482.1 (363.46)
Week 16	1566.0 (586.11)

2. Secondary Outcome

Title	Study Drug Related Adverse Events
Description	Safety will be evaluated on the incidence of AEs and clinically significant changes in vital signs as well as clinical labs and ECG. Please refer to AE section below for comprehensive listing of all adverse events recorded during study.
Time Frame	Weekly

Outcome Measure Data

Analysis Population Description

The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).

Arm/Group Title	Total
Arm/Group Description	The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
Measure Participants	16
Count of Participants [Participants]	16 100%

3. Secondary Outcome

Title	Percentage of Participants With PAL IgG Antibody Percentage of Participants With Positive PAL IgG
Description	Antibody against phenylalanine ammonia lyase (PAL)
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).

Arm/Group Title	Total
Arm/Group Description	rAvPAL-PEG in all doses.
Measure Participants	16
Baseline	12.5
Week 16	100.0

4. Secondary Outcome

Title	Plasma Concentrations of rAvPAL-PEG (BMN 165)
Description	Measurements taken pre-dose
Time Frame	Baseline, Week 8, Week 13

Outcome Measure Data

Analysis Population Description

The PK population will consist of all subjects who received any amount of study drug and have post-treatment plasma BMN 165 concentration measurements.

Arm/Group Title	rAvPAL-PEG
Arm/Group Description	rAvPAL-PEG in varying doses rAvPAL-PEG: 0.06 mg/kg/day, 0.1 mg/kg/day, 0.2 mg/kg/day, 0.4 mg/kg/day, 0.6 mg/kg/day, 0.8 mg/kg/day
Measure Participants	16
Baseline-Day 1, 1 Hour Predose	0.000 (0.0000)
Week 8-Day 52, 1 Hour Predose	2425.608 (8532.2431)
Week 13-Day 89, Predose	1116.364 (2013.9676)

5. Secondary Outcome

Title	Percentage of Participants With PEG-IgG Antibody Positivity
Description	Antibodies against polyethylene glycol (PEG) of the IgG isotype
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).

Arm/Group Title	Total
Arm/Group Description	The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
Measure Participants	16
Baseline	25.0
Week 16	75.0

6. Secondary Outcome

Title	Percentage of Participants With PAL-IgM Antibody Positivity
Description	Antibodies against phenylalanine ammonia lyase (PAL) of the IgM isotype
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).

Arm/Group Title	Total
Arm/Group Description	The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
Measure Participants	16
Baseline	12.5
Week 16	75.0

7. Secondary Outcome

Title	Percentage of Participants With PEG-IgM Antibody Positivity
Description	Antibodies against polyethylene glycol (PEG) of the IgM isotype
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).

Arm/Group Title	Total
Arm/Group Description	The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
Measure Participants	16
Baseline	31.3
Week 16	50.0

8. Secondary Outcome

Title	Percentage of Participants With Neutralizing Antibody Positivity
Description	Antibody positivity over time
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).

Arm/Group Title	Total
Arm/Group Description	The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
Measure Participants	16
Baseline	0.0
Week 16	0.0

9. Secondary Outcome

Title	Percentage of Participants With PAL-IgE Antibody Positivity
Description	Antibodies against phenylalanine ammonia lyase (PAL) of the IgE isotype
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).

Arm/Group Title	Total
Arm/Group Description	The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
Measure Participants	16
Baseline	0.0
Week 16	0.0

10. Secondary Outcome

Title	Percentage of Participants With PAL-PEG-IgE Antibody Positivity
Description	Antibodies against phenylalanine ammonia lyase (PAL)-polyethylene glycol (PEG) of the IgE isotype
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).

Arm/Group Title	Total
Arm/Group Description	The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
Measure Participants	16
Baseline	0.0
Week 16	0.0

Adverse Events

Time Frame	Week 0- Week 16
Arm/Group Title	rAvPAL-PEG
Arm/Group Description	rAvPAL-PEG in varying doses
All Cause Mortality
	rAvPAL-PEG
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Serious Adverse Events
	rAvPAL-PEG
	Affected / at Risk (%)	# Events
Total	1/16 (6.3%)
Skin and subcutaneous tissue disorders
Angioedema	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	rAvPAL-PEG
	Affected / at Risk (%)	# Events
Total	16/16 (100%)
Blood and lymphatic system disorders
Anaemia	1/16 (6.3%)	1
Thrombocytopenia	1/16 (6.3%)	1
Cardiac disorders
Tachycardia	1/16 (6.3%)	2
Ear and labyrinth disorders
Ear pain	1/16 (6.3%)	1
Ear pruritus	1/16 (6.3%)	1
Motion sickness	1/16 (6.3%)	1
Eye disorders
Eye pain	1/16 (6.3%)	1
Ocular hyperaemia	1/16 (6.3%)	1
Vision blurred	1/16 (6.3%)	1
Gastrointestinal disorders
Abdominal discomfort	2/16 (12.5%)	2
Abdominal pain	3/16 (18.8%)	3
Abdominal pain upper	1/16 (6.3%)	1
Constipation	1/16 (6.3%)	1
Diarrhoea	5/16 (31.3%)	9
Dry mouth	1/16 (6.3%)	1
Dyspepsia	4/16 (25%)	5
Flatulence	1/16 (6.3%)	1
Food poisoning	1/16 (6.3%)	1
Gastrooesophageal reflux disease	1/16 (6.3%)	1
Nausea	4/16 (25%)	5
Toothache	1/16 (6.3%)	1
General disorders
Chest discomfort	3/16 (18.8%)	3
Chills	3/16 (18.8%)	4
Fatigue	2/16 (12.5%)	2
Hangover	1/16 (6.3%)	1
Infusion site erythema	2/16 (12.5%)	8
Injection site bruising	6/16 (37.5%)	11
Injection site erythema	8/16 (50%)	18
Injection site induration	1/16 (6.3%)	2
Injection site nodule	1/16 (6.3%)	1
Injection site oedema	1/16 (6.3%)	1
Injection site pain	7/16 (43.8%)	9
Injection site pruritus	1/16 (6.3%)	1
Injection site rash	4/16 (25%)	8
Injection site reaction	8/16 (50%)	32
Injection site swelling	1/16 (6.3%)	1
Injection site urticaria	4/16 (25%)	10
Injection site warmth	2/16 (12.5%)	3
Instillation site pruritus	1/16 (6.3%)	1
Non-cardiac chest pain	1/16 (6.3%)	6
Oedema peripheral	2/16 (12.5%)	2
Pain	1/16 (6.3%)	2
Pyrexia	5/16 (31.3%)	6
Swelling	1/16 (6.3%)	1
Vessel puncture site bruise	1/16 (6.3%)	1
Infections and infestations
Nasopharyngitis	2/16 (12.5%)	2
Pharyngitis	1/16 (6.3%)	1
Sinusitis	1/16 (6.3%)	1
Tooth infection	1/16 (6.3%)	1
Upper respiratory tract infection	1/16 (6.3%)	1
Injury, poisoning and procedural complications
Contusion	2/16 (12.5%)	2
Fall	1/16 (6.3%)	1
Muscle strain	1/16 (6.3%)	1
Post procedural haemorrhage	1/16 (6.3%)	1
Post-traumatic neck syndrome	1/16 (6.3%)	1
Investigations
Blood bilirubin increased	1/16 (6.3%)	1
C-reactive protein increased	3/16 (18.8%)	3
Complement factor C3 decreased	3/16 (18.8%)	3
Complement factor C4 decreased	2/16 (12.5%)	2
Complement factor decreased	1/16 (6.3%)	1
Complement factor increased	1/16 (6.3%)	1
Electrocardiogram ST segment depression	1/16 (6.3%)	1
Weight decreased	1/16 (6.3%)	1
Metabolism and nutrition disorders
Decreased appetite	2/16 (12.5%)	2
Hypokalaemia	2/16 (12.5%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	12/16 (75%)	36
Foot deformity	1/16 (6.3%)	1
Groin pain	2/16 (12.5%)	3
Joint stiffness	2/16 (12.5%)	3
Joint swelling	4/16 (25%)	5
Muscular weakness	1/16 (6.3%)	1
Musculoskeletal chest pain	1/16 (6.3%)	1
Musculoskeletal pain	3/16 (18.8%)	4
Musculoskeletal stiffness	3/16 (18.8%)	5
Myalgia	5/16 (31.3%)	6
Neck pain	3/16 (18.8%)	3
Pain in extremity	4/16 (25%)	5
Pain in jaw	1/16 (6.3%)	1
Plantar fasciitis	1/16 (6.3%)	1
Nervous system disorders
Burning sensation	1/16 (6.3%)	1
Clonus	1/16 (6.3%)	1
Dizziness	9/16 (56.3%)	14
Dizziness postural	1/16 (6.3%)	1
Headache	10/16 (62.5%)	34
Hyperreflexia	2/16 (12.5%)	2
Hypersomnia	1/16 (6.3%)	1
Hypoaesthesia	1/16 (6.3%)	1
Lethargy	1/16 (6.3%)	1
Migraine	3/16 (18.8%)	5
Paraesthesia	2/16 (12.5%)	3
Sciatica	1/16 (6.3%)	1
Sinus headache	1/16 (6.3%)	1
Somnolence	1/16 (6.3%)	1
Tremor	4/16 (25%)	5
Psychiatric disorders
Anxiety	1/16 (6.3%)	1
Nervousness	1/16 (6.3%)	1
Reproductive system and breast disorders
Uterine spasm	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	4/16 (25%)	5
Dyspnoea	4/16 (25%)	4
Hypopnoea	1/16 (6.3%)	1
Nasal congestion	2/16 (12.5%)	2
Oropharyngeal pain	3/16 (18.8%)	4
Rhinorrhoea	1/16 (6.3%)	1
Sinus congestion	2/16 (12.5%)	2
Sneezing	3/16 (18.8%)	3
Throat irritation	2/16 (12.5%)	3
Throat tightness	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/16 (6.3%)	1
Erythema	2/16 (12.5%)	5
Pruritus	3/16 (18.8%)	9
Pruritus generalised	2/16 (12.5%)	2
Rash	2/16 (12.5%)	2
Rash erythematous	3/16 (18.8%)	3
Rash generalised	6/16 (37.5%)	7
Rash macular	1/16 (6.3%)	2
Rash maculo-papular	2/16 (12.5%)	2
Urticaria	3/16 (18.8%)	3
Surgical and medical procedures
Endodontic procedure	1/16 (6.3%)	2
Vascular disorders
Flushing	1/16 (6.3%)	1
Orthostatic hypotension	1/16 (6.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.