The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis
Phase: PHASE2
Conditions: Psoriasis
Sponsor: University of Michigan

The Effect of Riboflavin on Moderate to Severe 
Plaque Type Psoriasis 
 
NCT02622386 
IRB Approval Date: February 6, 2019  
 
 
 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
 
 
Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
 
 
Version:   8 February 6, 2019 
 
 
 
 
Sponsor-Investigator and Principal Investigator 
Johann Gudjonsson, MD 
Department of Dermatology 
1910 A. Alfred Taubman Center 
1500 E. Medical Center Dr. 
Ann Arbor, MI 48109-5314 
Phone: (734) 936-4075 
Fax: (734) 936-6395 
 
 
Co-Investigators 
Yolanda Helfrich, MD 
Department of Dermatology, University of Michigan 
Michael Goldfarb, MD 
Department of Dermatology, University of Michigan 
        Ji Won Ahn, MD                    Department of Dermatology, University of Michigan 
        Jashua Bornstein, MD            Department of Dermatology, University of Michigan 
        Tom Raisanen, MD                Department of Dermatology, University of Michigan 
        Thomas Scharnitz, MD         Department of Dermatology, University of Michigan 
        Annette Sullivan, MD          Department of Dermatology, University of Michigan 
        Jordan Talia, MD 
        Department of Dermatology, University of Michigan 
        Kiyanna Williams, MD          Department of Dermatology, University of Michigan 
        Mio Nakamura, MD               Department of Dermatology, University of Michigan 
 
 
Study Site 
University of Michigan 
Department of Dermatology 
Program for Clinical Research in Dermatology 
Phone: (734) 936-4075

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
TABLE OF CONTENTS 
 
1 
SYNOPSIS ................................................................................................................... 4 
2 
BACKGROUND ......................................................................................................... 4 
3 
OBJECTIVES ............................................................................................................. 7 
3.1 
PRIMARY ENDPOINT ........................................................................................ 7 
3.2 
SECONDARY ENDPOINTS ................................................................................ 7 
4 
STUDY DESIGN ........................................................................................................ 7 
5 
INVESTIGATIVE PRODUCTS ............................................................................... 8 
5.1 
B2-400 ..................................................................................................................... 8 
5.2 
PLACEBO .............................................................................................................. 8 
5.3 
INVESTIGATIVE PRODUCT RECEIPT, LABELING AND 
STORAGE .............................................................................................................. 8 
5.4 
SOURCE ................................................................................................................. 8 
5.5 
CHARACTERISTICS OF STUDY GROUP ...................................................... 8 
5.5.1 
INCLUSION CRITERIA ................................................................................ 8 
5.5.2 
EXCLUSION CRITERIA............................................................................... 9 
6 
STUDY PROCEDURES .......................................................................................... 10 
6.1 
SCREENING........................................................................................................ 10 
6.2 
ADMISSION/DAY 0 ........................................................................................... 11 
6.3 
RETURN VISITS - WEEKS 2, 6, 12, 16, 18, 22 AND 28 ................................. 11 
6.4 
CLOSEOUT TELEPHONE CALL AT WEEK 32 .......................................... 12 
6.5 
PREMATURE WITHDRAWAL FROM STUDY ........................................... 14 
7 
LABORATORY ASSESSMENTS .......................................................................... 14 
8 
RISK AND RISK MITIGATION ........................................................................... 14 
9 
DRUG ACCOUNTABILITY .................................................................................. 15 
10  MONITORING PLAN.............................................................................................14 
11 STATISTICAL METHODS .................................................................................... 16 
12 REFERENCES ......................................................................................................... 17 
13 APPENDIX A – PSORIASIS AREA AND SEVERITY INDEX (PASI) ............ 19 
14 APPENDIX B - STATIC PHYSICIANS GLOBAL ASSESSMENT (SPGA) .... 20 
15 APPENDIX C - DERMATOLOGY LIFE QUALITY INDEX ............................ 20 
16 APPENDIX D - PRURITUS ASSESSMENT ........................................................ 23 
17 APPENDIX E – ADVERSE EVENTS LOG ........................................................ 243 
18 APPENDIX F - CONCOMMITANT MEDICATIONS LOG.............................. 25 
 
LIST OF TABLES 
 
Table 1.  
Time and Events Table ............................................................................ 13 
 
 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
1 SYNOPSIS 
 
The purpose of this investigation is to determine the anti-inflammatory effect of high-dose 
riboflavin supplementation on chronic plaque psoriasis. Up to fifty volunteers with chronic 
plaque psoriasis will be recruited for a double-blind, placebo-controlled 28 week prospective 
study with cross-over of both the intervention and control groups at the 12 week time mark. 
There will be a 4 week washout period when subjects crossover. Riboflavin will be dosed 
400 mg by mouth daily versus placebo. Throughout the study we will perform both clinical 
and laboratory assessments to measure response. Clinical assessment will include the 
Psoriasis-Area-and-Severity-Index (PASI), Physician Global Assessment (PGA), 
Dermatology -Life-Quality-Index (DLQI) and pruritus assessment will be performed at all 
clinical evaluations. Photographs of volunteers’ skin will be taken. Skin punch biopsies of 
psoriasis plaques and uninvolved skin will be performed at pre-determined time points 
throughout the study to measure metabolomics and RNA profiling as well as histologic 
markers. Patients will also have regular blood draws to follow plasma measurements of 
riboflavin and Flavin-adenine-dinucleotide (FAD). 
 
The primary objective is to demonstrate the superiority of riboflavin as compared to placebo 
at achieving a PASI 50 response (a 50% or greater improvement in PASI from baseline). 
Secondary objectives include, measuring the efficacy of the intervention at achieving a 
PGA, DLQI, or pruritus assessment score of 0/1. All statistics will be performed on a 
modified intent-to-treat population.   
 
2 BACKGROUND 
 
Psoriasis is a chronic immune-mediated skin disorder characterized by complex alterations 
in epidermal growth and differentiation with multiple biochemical and immunologic 
abnormalities. Characteristic lesions are well-demarcated, symmetrically distributed red 
plaques with silvery scale. In the United States, the prevalence of psoriasis is estimated to be 
2% and it affects over 4 million people. 1,2 Psoriasis patients suffer from reduced quality of 
life related to the discomfort, social stigma, and disability caused by their disease.2 The 
overall economic burden of psoriasis on the United States was recently estimated at 35.2 
billion dollars with 12.2 billion dollars attributed to incremental medical costs and the rest 
from productivity and health-related quality of life losses.2 There is no cure for psoriasis and 
treatment is directed at controlling patients’ symptoms. Current treatment options consist of 
topical steroids, phototherapy, topical vitamin D3 (or calcipotriol), methotrexate, and newer 
biologic agents.  
 
Amongst patients with skin disease, there is significant interest in using complementary 
alternative medicine and vitamins to treat their disease.3 Some of this interest is driven by 
the proven efficacy of calcipotriol ointment for the treatment of psoriasis. Randomized 
controlled trials have shown topical calcipotriol ointment to be equivalent to a Class V 
topical steroid and that it has an excellent safety profile.4-6 This efficacy and safety led the 
United States Food and Drug Administration to approve calcipotriol ointment for psoriasis 
treatment in 1993 and since that time it has been an important part of psoriasis treatment. 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
 
Given this interest in vitamin treatments and the proven efficacy of vitamin treatment for 
psoriasis we were intrigued when our laboratory work uncovered a significant decrease in 
riboflavin levels in psoriasis plaques. While measuring the metabolic profile of psoriasis 
plaques as compared to skin from healthy volunteers, we measured 400 fold less riboflavin 
in psoriatic plaques (Gudjonsson, unpublished findings).  Furthermore, exploring predicted 
drug targets using recent Genome-Wide-Association-Studies (GWAS) in psoriasis, two risk 
loci (ACOX1 and NOS2) are targets of flavin-adenine-dinucleotide (FAD) a metabolite of 
riboflavin.  Reviewing the medical literature, we found a number of case series from fifty to 
sixty years ago reporting improvement of psoriasis after riboflavin treatment.7-9 Our 
laboratory findings and these case reports prompted our interest in exploring the use of this 
vitamin to treat psoriasis. 
 
Riboflavin, commonly known as Vitamin B2, is a water-soluble vitamin found in all living 
cells as mono- or dinucleotides. It is part of the Flavin family of compounds, and is the 
necessary precursor of the biologically important flavin adenine dinucleotide (FAD) and 
flavin mononucleotide (FMN).10 While plants and many microorganisms may generate 
riboflavin de novo, animals rely on dietary sources that they then convert to FAD and 
FMN.11 In human diets, major sources include dairy products, eggs, grains, and green leafy 
vegetables.12 Once consumed, riboflavin is absorbed via a carrier-mediated mechanism in 
the proximal small intestine and then excreted in the urine.12 Riboflavin is not stored in the 
body making a constant dietary supply necessary. Worldwide, Riboflavin is a bulk 
commodity with about 3,000 metric tons produced per year.10 A majority of this production 
is directed towards animal husbandry with a minority used for human food 
supplementation.10  
 
The clinical effects of riboflavin supplementation on psoriasis were first explored in the 
1950s. In 1952, Dr. Maynard published a case series of 148 psoriasis patients he had 
injected with 5-10 mg of riboflavin intramuscularly once weekly and then followed 
clinically. Of those 148 patients, 24% had complete remission (“healed”), and 68% had at 
least a 50% improvement.  Only 7% of the patients failed to respond or had less than a 50% 
improvement. Maynard also sent surveys to 156 of his psoriasis patients that he had treated 
with riboflavin but whom he had not seen in clinic for two years. He received 50 survey 
cards back and, of those cards, 82% of patients reported they had “healed,” “improved with 
no relapse,” or “improved with partial relapse.” Only 18% of responders felt their disease 
was the same as before riboflavin treatment.7 
 
Maynard’s work was soon followed by other publications on the topic. In 1952, Sulzberger 
and Baer published their observations that riboflavin 30 mg by mouth daily did not help 
psoriasis.8 In contrast, in 1954, Italian investigators Montilli and Pisani reported that daily 
intramuscular injections of 10 mg of riboflavin either clinically cured or improved the 
disease in 33 out of 42 psoriasis.8 In 1956, Dr. Herbert Luscombe published a case series 
demonstrating that weekly intramuscular injections of 50 mg of riboflavin for 4 to 16 weeks 
“improved” or “markedly improved” 39 out of 44 psoriatic patients in his clinic.9 In 
contrast, in 1957, Drs. Welsh and Ede published a large case series of 348 psoriasis patients 
they treated with riboflavin and concluded “moderate and/or massive dosages” of riboflavin 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
failed to produce any significant response in those patients.8 To our knowledge, there have 
been no more published trials or case series on the clinical effects of treating psoriasis with 
riboflavin. Taken together we think the results of these trials are intriguing and create 
clinical equipoise on whether riboflavin is an effective treatment for psoriasis. 
 
While publications examining riboflavin and psoriasis largely stopped after the 1950s, 
neurologists became interested in whether riboflavin could be used to treat migraines in the 
1990s. We found three human trials published on the clinical effects of riboflavin on 
migraine headaches involving 152 human subjects. Two of these publications included the 
results from randomized controlled trials and the third was an open-label study. In these 
reports, subjects were followed for three to six months and all subjects in the intervention 
groups were administered riboflavin 400 mg by mouth daily either blinded or open-label - 
75 subjects total. Two of the studies observed a statistically significant and clinically 
meaningful improvement in the number of migraine attacks.13,14 The third study observed a 
statistically significant placebo effect and so found no benefit to the intervention. 
Interestingly, the blinded placebo in this randomized controlled trial was riboflavin 25 mg 
by mouth daily, so the authors wondered if even this low dose of riboflavin was biologically 
active. This trial was stopped prematurely, because interim analysis demonstrated the 
intervention would not show a statistically significant result. The authors were unable to 
conclude whether the results with the lower-dose of riboflavin (the “placebo group”) were 
an active effect or a placebo effect.15 
 
Riboflavin was well tolerated by the subjects in these studies. Only two publications 
included data on adverse outcomes associated with riboflavin and within these trials there 
were five adverse events out of the 51 patients administered riboflavin. Adverse events 
included diarrhea (2 subjects), upper abdominal pain, facial erythema and polyuria.13,14 One 
subject who experienced diarrhea withdrew early from the trial but it was reported that her 
symptoms resolved within 72 hours.13 Both studies concluded that riboflavin was safe and 
well-tolerated. 
 
Finally, in ophthalmology, photoactivated riboflavin has been used for the last twelve years 
to treat structural deformities and inflammatory conditions of the cornea such as, 
keratoconus, keratectasia, and infectious keratitis.16-18 In this technique the corneal 
epithelium is removed, riboflavin is applied and the tissue is irradiated with ultraviolet A 
light.17 The riboflavin strengthens the collagen in the cornea and biochemically stabilizes the 
layer to prevent further complications from these conditions.16,17 
 
In conclusion, psoriasis is a common and socially stigmatizing condition in the United 
States. Our laboratory metabolomics profiling has shown that psoriasis plaques have 
significantly less riboflavin than healthy controls. Previous human case reports suggest that 
riboflavin is clinically effective for the treatment of psoriasis; however, they were not 
conclusive. More recent human trials have shown that 400 mg of daily oral riboflavin is a 
safe and well-tolerated medication to administer to humans. Our laboratory data, the 
published case reports of riboflavin’s effectiveness and its safety led us to propose these 
clinical and laboratory experiments to better determine riboflavin’s effects on psoriasis. 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
3 OBJECTIVES 
3.1 
Primary endpoint 
The number of subjects that achieve a 50 percent or greater reduction in their PASI with 
intervention as compared to placebo. 
 
3.2 
Secondary endpoints 
• The number of subjects that achieve a PASI 75, 90, 100 response with 
intervention as compared to placebo. 
• The number of subjects that achieve a PGA score of 0/1 with intervention as 
compared to placebo. 
• The number of subjects that report a pruritus score of 0/1 with intervention 
as compared to placebo. 
• The number of subjects treated that report a DLQI score of 0/1 with 
intervention as compared to placebo. 
• The difference in serum plasma levels of riboflavin and FAD in subjects 
treated with intervention as compared to placebo. 
 
4 STUDY DESIGN  
 
A 28-week, double-blind, placebo-controlled, prospective study with cross-over of both the 
riboflavin and placebo groups at the 12-week time mark.  
 
Patients will take either 400 mg of riboflavin (“B2-400”) or a placebo by mouth once a day 
for 12 weeks. There will be a four week wash-out period at week 12 as the groups cross-
over.  
 
We propose using a 400 mg daily dose in this clinical trial as there is the most evidence in 
previous human studies for a clinical effect with this dose. While data suggesting equivalent 
activity of riboflavin at a lower dose is intriguing, we feel it is premature to choose a lower 
dose based off the findings in one trial that was stopped prematurely.15 
 
Up to 50 subjects will be enrolled. Six skin biopsies will be performed to measure 
metabolomics profiles, and there will be five blood draws to measure serologic markers. 
 
 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
 
5 INVESTIGATIVE PRODUCTS 
5.1 
B2-400 
 
B2-400 is a clear gelatin two-piece capsule, size 00, filled with yellow-orange powder 
equaling 400 mg of Riboflavin (Vitamin B2). The near-infrared spectra of the powder 
matches the reference standard for riboflavin. The only inactive ingredient is the gelatin in 
the capsule which is kosher and halal certified. It will be manufactured by Biotech 
Pharmacal, Inc., Fayetteville, AR. The capsule is to be swallowed whole with food. Product 
testing shows it meets USP specifications for weight, heavy metals and Prop 65 
specifications for heavy metals. 
5.2 
Placebo 
 
Placebo will consist of a clear gelatin two-piece capsule, size 2, filled with white powder. 
There will be no active ingredients. Inactive ingredients include the gelatin capsule, which is 
kosher and halal certified, as well as microcrystalline cellulose powder. It will be 
manufactured by Biotech Pharmacal, Inc., Fayetteville, AR. The capsule is to be swallowed 
whole with food. Product testing shows it meets USP specifications for weight, heavy metals 
and Prop 65 specifications for heavy metals. 
 
5.3 
Investigative Product Receipt, Labeling and Storage 
 
All study medications (B2-400 and placebo) will be received, stored, and dispensed by the 
University of Michigan Health System Research Pharmacy (UH B2D301). Block 
randomization will be used, as outlined in the statistics section below, and shared with the 
UMHS Research Pharmacy for proper dispensing of investigational products. 
5.4 
Source 
Study subjects will be recruited from the University of Michigan Department of 
Dermatology outpatient clinics, and/or local announcement. 
 
5.5 
Characteristics of Study Group 
Subjects will include up to 50 male or female subjects, 18 years of age or older, of any racial 
or ethnic background, and in good general health with chronic plaque psoriasis. 
 
5.5.1 
Inclusion Criteria 
 
Subjects must meet all of the following criteria for inclusion in the study: 
1. 18 years of age or older 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
2. Good general health 
3. Willingness and ability to follow the protocol 
4. Signed Informed Consent Form, written and witnessed. 
5. Stable moderate to severe chronic plaque psoriasis involving 5% or greater total body 
surface area (TBSA). 
6. If subject is a woman of childbearing potential, she must have a negative pregnancy test 
at screening and agree to use a medically acceptable form of contraception during the 
screening and throughout the study. 
 
5.5.2 
Exclusion Criteria 
 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Started using a topical steroid stronger than moderate strength, vitamin A or D analog 
preparations, or anthralin within 14 days of study drug initiation. 
2. Initiated a systemic medications, including biologic medication, or phototherapy within 
180 days of study drug initiation. 
3. Prior or concurrent use of cyclophosphamide. 
4. Currently using sulfasalazine therapy. 
5. Known hypersensitivity to riboflavin. 
6. Enrolled in any other investigational device or investigational drug trial(s) or receipt of 
any other investigational agent(s) within 28 days of baseline visit. 
7. Presence of severe comorbidities such as, diabetes mellitus requiring insulin; CHF of 
any severity or myocardial infarction or cerebrovascular accident or transient ischemic 
attack within 3 months of screening visit; unstable angina pectoris, uncontrolled 
hypertension [sitting systolic BP <80 mm Hg or > 160 or diastolic BP > 100 mm Hg], 
oxygen-dependent severe pulmonary disease, history of cancer within 5 years [other than 
resected cutaneous basal or squamous cell carcinoma of the skin or in situ cervical 
cancer]. 
8. Any of the following hematologic abnormalities, confirmed by repeat test at least 1 week 
apart: 
• White blood count <3,000/µL or >14,000/µL 
• Lymphocyte count <1,000/µL 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
• Neutrophil count <1,5000/µL 
• Platelet count <150,000/µL 
• Hemoglobin<10 g/dL 
9. Liver function test (aspartate aminotransferase [AST], alanine aminotransferase [ALT] 
or alkaline phosphatase [AlkP]) results that are greater than or equal to 2 times the upper 
limit of normal (ULN). 
10. Serum creatinine ≥ to 2x the ULN. 
11. Known HIV-positive status or known history of any other immune-suppressing disease. 
12. Any current or past history of psychiatric disease that would interfere with ability to 
comply with study protocol or give informed consent. 
13. Had grade 3 or 4 adverse events or infections within 28 days before screening, or 
between screening visit and drug initiation. 
14. Evidence of any skin conditions other than psoriasis that would interfere with the 
evaluations of the effect of study medication on psoriasis. 
15. Presence of any condition or circumstances judged by the patient’s physician, the 
investigator, or medically qualified study staff to render this clinical trial detrimental or 
otherwise unsuitable for the patient’s participation. 
16. A history of non-compliance with other therapies. 
17. Females who are pregnant, lactating, planning on pregnancy during the study period, or 
unwilling to use FDA-approved method of birth control. 
18. A history of keloids or excessive scar formation or of healing poorly 
19. A history of allergic reaction to local anesthetics, including lidocaine and epinephrine 
  
6 STUDY PROCEDURES 
 
6.1 
Screening 
 
The following are to be performed within 2 weeks prior to admission/Day 0: 
1. Obtain written, witnessed informed consent 
2. Review inclusion/exclusion criteria 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
3. Obtain complete medical history, history of previous psoriasis therapies, concomitant 
medications, and physical examination 
4. For females of childbearing potential, obtain a negative urine pregnancy test. 
5. Obtain 9 mL of blood to measure a complete blood count (CBC) and comprehensive 
metabolic panel (CMP). 
 
6.2 
Admission/Day 0 
1. Measure vital signs. 
2. Review medical history, adverse events and concomitant medications. 
3. Skin Exam: Complete PASI, PGA, DLQI, and pruritus assessment using visual analog 
scale (VAS). 
4. Photographs will be taken of significant lesions. 
5. Randomize patient 
6. For females of childbearing potential, obtain a negative urine pregnancy test. 
7. 20 mL of blood will be drawn for measuring plasma levels of riboflavin and FAD.  
8. Two psoriatic normal (PN) and two psoriatic plaque (PP) skin samples will be obtained 
(four total at this visit).  These will be performed under local anesthesia (1% lidocaine 
with epinephrine) using a 6 mm skin punch to obtain skin through to subcutaneous fat.  
Closures will be made with 4-0 prolene sutures that should be removed in two weeks. 
Verbal wound care instructions will be provided.  
9. Dispense medication. 
  
6.3 
Return Visits - Weeks 2, 6, 12, 16, 18, 22 and 28 
1. Measure vital signs. 
2. Review medical history, adverse events and concomitant medications. 
3. Skin Exam: Complete PASI, PGA, DLQI, and pruritus assessment using visual analog 
scale (VAS). 
4. For females of childbearing potential, obtain a negative urine pregnancy test. 
5. Photographs will be taken of significant lesions on weeks 0, 12, 16, and 28. 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
6. One PP and one PN 6 mm punch biopsy will be performed at week 12. These will be 
performed as described above. This will be a total of 6 biopsies throughout the study. 
7. 20 mL of blood will be drawn for measuring plasma levels of riboflavin and FAD on 
weeks 2, 12, 18 and 28.  
8. 9 mL of blood will be drawn for measuring CBC, CMP on weeks 12 and 28. 
9. At week 12 all residual medication will be collected and counted in preparation for 
patients to cross-over. There will be a four week wash-out period between weeks 12 and 
16. At week 16 new medication will be provided and the data from this visit will be used 
as our new baseline for the second part of the study. 
10. At week 28, all residual medication will be collected and counted. 
 
6.4 
Closeout Telephone Call at Week 32 
 
1. Review medical history, adverse events, and concomitant medications. 
 
2. Offer patient an in-office visit for any adverse events identified. 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
Table 1.  
Time and Events Table 
 
Screening 
Week 0 
Week 2 
Week 6 
Week12 
Week 16 
Week 18 
Week 22 
Week 28 
Week 32 
(phone) 
Obtain informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Medical  and Psoriatic 
Treatment History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Con Meds/AE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PASI, PGA 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
DLQI/ Pruritus VAS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine Pregnancy Test 
for WOCBP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Draw 
(CBC/CMP) 
X 
 
 
 
X 
 
 
 
X 
 
Blood Draw (FAD and 
Riboflavin) 
 
X 
X 
 
X 
 
X 
 
X 
 
Biopsies 
 
X 
 
 
X 
 
 
 
 
 
Photographs 
 
X 
 
 
X 
X 
 
 
X 
 
Collect Residual 
Medication 
 
 
 
 
X 
 
 
 
X 
 
Dispense New 
Medication 
 
X 
 
 
 
X 
 
 
 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
 
6.5 
Premature Withdrawal from Study 
Any subject who experiences adverse effects associated with study participation may be 
withdrawn from the study.  Participation in the study may be discontinued for any of the 
following reasons:  
1. Adverse events 
2. Concurrent illness 
3. Pain or discomfort during the study 
4. Administrative reasons 
5. Subject’s decision to withdraw consent 
6. Protocol violation.   
 
Complete information on all adverse events will be recorded on an Adverse Event Report form 
(see Appendix E – Adverse Events LOG for a possible example). The Sponsor-Investigator will 
review all Adverse Events. The investigator will report adverse events that meet the standard 
IRBMED reporting guidelines (regarding relatedness and expectedness) to the University of 
Michigan Institutional Review Board and to the FDA as outlined in 21 CFR 312.32. 
 
7 LABORATORY ASSESSMENTS 
 
Biopsies will be processed for metabolomic profiling and will be taken from psoriatic normal 
(PN) as well as psoriatic plaque (PP) skin. Six 6 mm punch biopsies of the skin will be 
performed on each subject throughout the study. Two PN and two PP biopsies will be performed 
on week 0. Then one PN and one PP biopsy will be performed at week 12. For each subject, we 
will attempt to obtain all biopsies from the same plaque and the same area of normal skin. These 
biopsies will be divided in half and used for RNA profiling and histology.  
 
Histological assessment will be performed for all patients using H&E, proliferation markers 
(Ki67), keratin 16, human beta defensin 2 (hBD2).  Samples will be processed in batches of 10 
patients at a time to limit batch-to-batch variation.  To determine tissue responses, we will run a 
total of 20 patients for metabolomic and RNA-seq profiling.  
 
All subjects will have a CBC, CMP drawn on screening and then at weeks 12, and 28. All 
patients in the study will have plasma measurements of riboflavin and FAD at weeks 0, 2, 12, 18, 
and 28. This will be a total of approximately 127 mL of whole blood per subject.  
 
8 RISK AND RISK MITIGATION 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
The risks to subjects in this study are minimal, as riboflavin is a common over-the-counter 
supplement and the dose in this study has been well tolerated in previous studies (see 
Background Information). Side effects of diarrhea and polyuria have been reported, but these 
resolved promptly with discontinuation of riboflavin. There have been no reported deaths. 
Riboflavin toxicity is unlikely and also reversed promptly by discontinuation of the vitamin.  
 
At study visits and the close-out telephone call, all subjects will be screened for adverse events. 
Any reported events will be recorded on a standardized form, similar to the example included in 
Appendix E – Adverse Events LOG. Basic labs will be drawn throughout the study, CBC and 
CMP, to monitor for potential toxicity to subjects’ bone marrow, liver and kidneys. Pregnancy 
tests will be administered at each office visit to women of childbearing potential. As this dose of 
riboflavin has not been studied in pregnant women, any woman who becomes pregnant during 
the study will be discontinued. 
 
Serious adverse events will be reported according to the UM IRB protocol in an expedited 
manner. These events include any untoward medical occurrence that results in: death, life 
threatening illness, hospitalization, persistent disability/incapacity, pregnancy, congenital 
anomaly/birth defect, an important medical event as deemed by the study investigators. Study 
investigators and staff will work together in this reporting. 
9 DRUG ACCOUNTABILITY 
 
Study administrators, Ms. Katherine Keeley and Jennifer Bell, will communicate with UMHS 
Pharmacy and coordinate the delivery of investigational medications. All investigational 
medications will be stored and dispensed to study administrators by the UMHS Research 
Pharmacy (UH B2D301), per protocol. These administrators will then hand subjects the 
investigational medication. At weeks 12 and 28, the study administrators will receive any excess 
investigational medication and record the number of returned capsules in the subjects file. 
 
10 MONITORING PLAN 
A risk-based approach to monitoring will be used for this study. The study has been assigned a 
risk level of "minor increase over minimal risk" with the University of Michigan Institutional 
Review Board (IRBMED).  The study drug being used has a Generally Recognized as Safe 
(GRAS) designation from FDA and the Select Committee on GRAS (SCOGS) concluded that 
there is no hazard to the public when it is used at levels currently recommended by the FDA.  
This is a non-complex study that involves otherwise healthy subjects who are to be seen in an 
established and experienced research environment, with no electronic data capture using 
relatively safe study drug. For these reasons, the following monitoring plan will be implemented. 
An onsite, independent, trained and experienced internal monitor will be assigned to monitor the 
progress of the study.  The monitor will use existing standard departmental standards and 
guidelines in conducting the study review. The frequency of the review will be dependent on 
study activity, but will occur at least yearly. The first review will take place no more than 2 
months from the enrollment of the first subject.   

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
Processes/documentation to be reviewed by the monitor include:  
• Communication between site staff IRBMED and subjects 
•  Verification of informed consent 
•  Adherence to protocol eligibility criteria 
• Adherence to current documented protocol procedures 
• Source documentation accuracy and completeness 
•  Procedures for documenting appropriate accountability and administration of the study 
drug 
• Review adverse event reporting 
 
Monitor will provide written results of the review including enrollment status, a description of 
any noncompliance or data irregularities, and any required corrective actions for significant 
issues found.  Monitor will also confirm corrective actions were implemented and that reportable 
occurrences were reported to IRBMED. These reports will be submitted to IRBMED at the 
scheduled continuation review.  
11 STATISTICAL METHODS 
 
A block randomization schedule will be created and all subjects randomly assigned to a sequence 
of treatment and dispensed study product.  Assuming a large effect size and a conservative 
amount of correlation between the measurements, a sample size of 22 subjects in each sequence 
yields a statistical power of 80%.   
 
All clinical and laboratory assessments will be descriptively summarized at each visit (weeks 0, 
2, 12, 16, 18, and 28) for the modified intent-to-treat population.  Continuous variables will be 
summarized with standard descriptive statistics including mean, standard deviation and range. 
Categorical variables will be summarized by frequency and percentage (N, %).   
 
Differences within each sequence of treatment from baseline to endpoint will be assessed using 
parametric general linear models such as the paired t-test.  The two sequences will also be 
compared with respect to dichotomized improvement from baseline to the 12-week visit for key 
clinical endpoints using the McNemar test.  Assuming no carryover effects due to the four-week 
washout period, all data will be pooled and used to estimate the treatment effect.  An analysis 
testing the assumption of equal carryover effects will be performed.  Wilcoxon signed rank test 
will be used to compare ordinal or nominal assessments.  Parametric t-tests will be used to 
determine if continuous laboratory assessments are significantly different between the treatment 
groups.   
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
An overall alpha-level of 0.05 will be used to determine statistical significance and all statistical 
tests will be two-sided.  All data will be analyzed using SAS (SAS Institute, Inc., Version 9.3) 
software. 
 
12 REFERENCES 
 
1. 
Fowler JF, Duh MS, Rovba L, et al. The impact of psoriasis on health care costs and 
patient work loss. Journal of the American Academy of Dermatology 2008;59:772-80. 
2. 
Vanderpuye-Orgle J, Zhao Y, Lu J, et al. Evaluating the economic burden of psoriasis in 
the United States. Journal of the American Academy of Dermatology 2015;72:961-7 e5. 
3. 
Smith N, Shin DB, Brauer JA, Mao J, Gelfand JM. Use of complementary and alternative 
medicine among adults with skin disease: results from a national survey. Journal of the American 
Academy of Dermatology 2009;60:419-25. 
4. 
Dubertret L, Wallach D, Souteyrand P, et al. Efficacy and safety of calcipotriol (MC 903) 
ointment in psoriasis vulgaris. A randomized, double-blind, right/left comparative, vehicle-
controlled study. Journal of the American Academy of Dermatology 1992;27:983-8. 
5. 
Cunliffe WJ, Berth-Jones J, Claudy A, et al. Comparative study of calcipotriol (MC 903) 
ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. Journal of 
the American Academy of Dermatology 1992;26:736-43. 
6. 
Ramsay CA, Berth-Jones J, Brundin G, et al. Long-term use of topical calcipotriol in 
chronic plaque psoriasis. Dermatology 1994;189:260-4. 
7. 
Maynard MT. Psoriasis treated by riboflavin. The Journal of investigative dermatology 
1952;18:305-6. 
8. 
Welsh AL, Ede M. An appraisal of the therapeutic effect of riboflavin in psoriasis. AMA 
archives of dermatology 1957;76:595-9; discussion 9-600. 
9. 
Luscombe HA. Riboflavin in psoriasis. AMA archives of dermatology 1956;74:548-9. 
10. 
Edwards AM. Flavins and Flavoproteins. New York: Springer Science+Business Media. 
11. 
Ilka Haase TG, Boris Illarionov, Adelbert Bacher,, Fischer aM. Flavins and 
Flavoproteins. New York: Springer Science+Business Media. 
12. 
Chawla J, Kvarnberg D. Hydrosoluble vitamins. Handbook of clinical neurology 
2014;120:891-914. 
13. 
Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine 
prophylaxis. A randomized controlled trial. Neurology 1998;50:466-70. 
14. 
Boehnke C, Reuter U, Flach U, Schuh-Hofer S, Einhaupl KM, Arnold G. High-dose 
riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care 
centre. European journal of neurology : the official journal of the European Federation of 
Neurological Societies 2004;11:475-7. 
15. 
Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and 
feverfew for migraine prophylaxis: a randomized trial. Headache 2004;44:885-90. 
16. 
Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking 
for the treatment of keratoconus. American journal of ophthalmology 2003;135:620-7. 
17. 
Said DG, Elalfy MS, Gatzioufas Z, et al. Collagen cross-linking with photoactivated 
riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. 
Ophthalmology 2014;121:1377-82. 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
18. 
Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen crosslinking with 
riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. Journal 
of cataract and refractive surgery 2007;33:2035-40. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
13 Appendix A – Psoriasis Area And Severity Index (PASI) 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
14 Appendix B - Static Physicians Global Assessment (sPGA)  
 
Static Physicians Global Assessment (sPGA)  
The sPGA is used to determine a subject’s psoriasis lesions overall at a given time point. The 
sPGA score should be selected using the descriptors below that best describe the overall 
appearance of the lesions. It is not necessary that all three criteria be fulfilled.  In some subjects 
either scaling or erythema will dominate the clinical presentation.  In those cases, the sPGA 
score should be based on a combination of plaque elevation and the dominant feature (either 
erythema or scale). Since plaque elevation is the most robust finding, it should be the dominant 
feature influencing the sPGA rating for those indeterminate cases.  
 
Score 
Category Category Description 
0 
Clear 
Plaque elevation = 0 (no elevation over normal skin) Scaling = 0 (no 
scale) 
Erythema = 0 (residual post-inflammatory hyperpigmentation or 
hypopigmentation may be present) 
1 
Minimal 
Plaque elevation = 
(possible but difficult to ascertain whether there is a slight 
elevation above normal skin) 
Scaling = 
(surface dryness with some white coloration) Erythema = up to 
moderate (up to definite red coloration) 
2 
Mild 
Plaque elevation = slight (slight but definite elevation typically edges are indistinct 
or sloped) 
Scaling = fine (fine scale partially or mostly covering lesions) Erythema = up to 
moderate (up to definite red coloration) 
3 
Moderate 
Plaque elevation = moderate (moderate elevation with rough or sloped edges) 
Scaling = coarser (coarse scale covering most of all of the lesions) Erythema = moderate 
(definite red coloration) 
4 
Severe 
Plaque elevation = marked (marked elevation typically with hard or sharp edges) 
Scaling = coarse (coarse, non-tenacious scale predominates covering most or all 
of the lesions) 
Erythema = severe (very bright red coloration) 
5 
Very Severe 
Plaque elevation = very marked (very marked elevation typically with hard sharp 
edges) 
Scaling = very coarse (coarse, thick tenacious scale covering most of all of the 
lesions; rough surface) 
Erythema = very severe (extreme red coloration; dusky to deep red coloration) 
 
Physician’s sPGA: _____________    
Evaluator’s Initials:_____________ 

Title:  T he Effect of Ri b ofla vi n o n M o derate t o Se vere Pla q ue T y pe Ps oriasis  
Pri nci p al I n vesti g at or:  J o ha n n G u dj o nss o n, M D 
 
Versi o n 8  Fe br uar y 6, 2 0 1 9 – u p date d C o-I D ec. 2 0 1 9 
 
 
1 5  A p p e n di x C - Der m at ol o g y  Lif e Q u alit y In d e x  
 
D E R M A T O L O G Y LI F E Q U A LI T Y I N D E X  
D L QI  
H os pital N o:   
  
  
  
 
Date:     
  
  
  
  
 
Na me:     
  
  
  
  
  
  
  
 
Sc ore:  
A d dress:   
  
  
  
  
Dia g n osis:  
  
  
  
 
 
 
T he ai m of t his q uesti o n n aire is t o m e as ure h o w m uc h y o ur s ki n pr o ble m h as affecte d y o ur life O V E R 
T H E L A S T W E E K.  Ple ase tic k o ne b o x f or e ac h q uesti o n.  
 
1.  
O ver t he last wee k, h o w itc h y, s ore,   
  
 
Ver y m uc h  
 
 
p ai nf ul  or sti n gi n g has y o ur s ki n    
  
 
A l ot   
 
 
 
bee n ?     
  
  
  
  
 
A little    
 
  
  
  
  
  
  
  
 
N o t at all 
 
 
2.  
O ver t he last wee k, h o w e m b arr asse d  
  
 
Ver y m uc h  
 
 
or self c o nsci o us ha ve y o u bee n beca use     
 
A l ot   
 
 
  
of y o ur s ki n?  
  
   
  
  
 
A little    
 
  
  
  
  
  
  
  
 
N o t at all 
 
 
3.  
O ver t he last wee k, h o w m uc h has y o ur     
 
Ver y m uc h  
 
  
s kin i nterfere d wit h y o u g oi n g  
  
   
 
A l ot   
 
 
 
s h op pi n g  or l o o ki n g after y o ur h o m e  or     
 
A little    
 
 
g a r de n?         
  
  
  
  
 
N ot at all  
  
 
N o t rele va nt    
 
 
4.  
O ver t he last wee k, h o w m uc h has y o ur     
 
Ver y m uc h  
 
  
s kin i nfl ue nce d t he cl ot hes   
  
  
 
A l ot   
 
 
 
y o u we ar?  
  
  
  
  
 
A little    
 
  
  
  
  
  
  
  
 
N o t at all 
  
 
N o t rele va nt    
 
 
5.  
O ver t he last wee k, h o w m uc h has y o ur     
 
Ver y m uc h  
 
 
s ki n affecte d a n y s oci al or   
  
  
 
A l ot   
 
 
 
leisure  acti vities?  
  
  
  
 
A little    
 
  
  
  
  
  
  
  
 
N o t at all 
  
 
N o t rele va nt    
 
 
6.  
O ver t he last wee k, h o w m uc h has y o ur     
 
Ver y m uc h  
 
 
s ki n ma de it diffic ult f or    
  
  
 
A l ot   
 
 
  
y o u t o d o a n y s p ort?  
  
  
  
 
A little    
 
  
  
  
  
  
  
  
 
N o t at all 
  
 
N o t rele va nt    
 
 
7.   
O ver t he last wee k, has y o ur s ki n pre ve nte d   
 
Yes   
 
 
  
y o u fro m w or ki n g  or st u d yi n g?    
  
 
N o   
 
  
 
N o t rele va nt    
 
  
 
  
If " N o", o ver t he last wee k h o w m uc h has    
 
A l ot   
 
 
  
y o ur ski n bee n a pr o ble m at   
  
  
 
A little    
 
 
w o r k or st u d yi n g?  
  
  
  
 
N ot at all  
 
 

Title:  T he Effect of Ri b ofla vi n o n M o derate t o Se vere Pla q ue T y pe Ps oriasis  
Pri nci p al I n vesti g at or:  J o ha n n G u dj o nss o n, M D 
 
Versi o n 8  Fe br uar y 6, 2 0 1 9 – u p date d C o-I D ec. 2 0 1 9 
 
 
8.   
O ver t he last wee k, h o w m uc h has y o ur     
 
Ver y m uc h  
 
  
ski n create d pr o ble ms wit h y o ur     
  
 
A l ot   
 
 
 
p art ner  or a n y of y o ur cl ose frie n ds  
  
 
A little    
 
 
o r rel ati ves?   
  
  
  
  
 
N ot at all  
  
 
N ot rele va nt  
 
 
9.   
O ver t he last wee k, h o w m uc h has y o ur     
 
Ver y m uc h  
 
  
ski n ca use d a n y se x u al     
  
  
 
A l ot   
 
 
 
d iffic ulties?  
  
  
  
  
 
A little    
 
  
  
  
  
  
  
  
 
N ot at all  
  
 
N ot rele va nt   
 
 
1 0.   
Over t he last wee k, h o w m uc h of a   
  
 
Ver y m uc h  
 
  
pro ble m has t he tre at m e nt f or y o ur  
  
 
A l ot   
 
 
  
ski n bee n, f or e xa m ple b y ma ki n g   
  
 
A little   
 
  
y o ur h o me mess y, or b y ta ki n g u p ti me?     
 
N ot at all  
  
 
N ot rele va nt    
 
 
P le ase c hec k y o u h a ve a ns were d E V E R Y q uesti o n. T h a n k y o u.  
A Y Fi nla y, G K K ha n, A pril 1 9 9 2  w w w. der mat ol o g y. or g. u k , this m ust n ot be c o pie d wit h o ut t he per missi o n of t he a ut h ors. 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
16 Appendix D - Pruritus Assessment 
 
Pruritus Assessment 
Please rate your itch over the last 24 hours from 1-10 (10 being the worst)? 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
17 APPENDIX E – ADVERSE EVENTS LOG 
 
Did the subject have any pre-existing conditions or experience any AEs while in the study?      
YES                NO 
 
Event 
Term 
Start 
Date 
and 
Time 
End 
Date 
Severity 
 
 
Outcome 
Possibly 
related to 
study drug? 
Possibly 
related to 
study 
procedure? 
Serious? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEVERITY:   MILD, MODERATE, SEVERE          IF SEVERITY CHANGES, INDICATE DATE OF 
CHANGE AND NEW SEVERITY: MILD, MODERATE, SEVERE, MORE SEVRE THAN BASELINE               
OUTCOME:  RESOLVED, RESOLVING, NOT RESOLVED, RECOVERED WITH SEQUELAE, FATAL, 
DISABILITY/INCAPACITY, WORSENED,  UNKNOWN  
IF SERIOUS, INDICATE ALL THAT APPLY: DEATH, LIFE THREATENING, DISABILITY, 
HOSPITALIZATION, CONGENITAL ANOMALY, OTHER, REQUIRES INTERVENTION 
 

Title: The Effect of Riboflavin on Moderate to Severe Plaque Type Psoriasis 
Principal Investigator: Johann Gudjonsson, MD 
 
Version 8  February 6, 2019 – updated Co-I Dec. 2019 
 
 
18 APPENDIX F - CONCOMMITANT MEDICATIONS LOG 
Did the subject take any concomitant medications while in the study?       YES                NO 
Treatment 
Name 
Start 
Date 
End 
Date 
Dose 
Dose 
Unit 
Treatment 
Frequency 
Route 
Indication* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*specify if primary study condition, prophylaxis or non therapeutic, pre-existing condition, or adverse event