Conditions: Candidiasis, Chronic Mucocutaneous
Keywords: STAT3 deficient Hyper IgE syndrome Gain of function STAT1 defects Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) IL-17/IL-22 autoantibodies from thymoma Job's Syndrome (Hyperimmunoglobulin E Syndrome, Buckley Syndrome)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
This is an open-label, dose-titration trial to study the efficacy, safety, and pharmacokinetics of oral cochleate amphotericin B (CAMB) in the treatment of mucocutaneous candidiasis infections in patients who are refractory or intolerant to standard non intravenous therapies.

Detailed description:
Patients aged 18 to 75 years with mucocutaneous candidiasis (esophageal, oropharyngeal, or vulvovaginal) who are refractory or intolerant to standard non-intravenous therapies will be enrolled. Patients will initially be treated in a short-term dose titration period, where the dose may be increased in patients that do not respond clinically. Patients who do not respond clinically to the highest dose of drug will discontinue the protocol. Patients that respond to treatment and tolerate the study medication will be eligible to enter a long-term extension (up to 60-months).

Arms:
arm 1: Encochleated Amphotericin B (200 mg, 400 mg, 800 mg)

Interventions: intervention 1: Amphotericin B
Intervention descriptions: intervention 1: Oral lipid nanocrystal formulation of amphotericin B

Protocol document:
Prot_SAP_001.pdf: 
A Phase IIa Efficacy, Safety, Tolerability and 
Pharmacokinetic Study of Encochleated Amphotericin B 
(CAMB) in Patients with Mucocutaneous (Esophogeal, 
Oropharyngeal, Vulvovaginal) Candidiasis Who are 
Refractory or Intolerant to Standard Non- Intravenous 
Therapies
Version Number: 17.0
NIH Protocol Number: 16-I-0002
Matinas BioPharma Nanotechnologies, Inc. Protocol Number: MB-70004 
Date: May 1, 2021
Principal Investigator: Alexandra Freeman, MD 
Laboratory of Clinical Immunology and Microbiology 
(LCIM)/NIAID Building 10 Room 11N234
10 Center Drive
Bethesda, MD 20814
Phone: 301-594-9045
Email: freemaal@mail.nih.gov
Pharmaceutical Support Provided by: Matinas BioPharma Nanotechnologies, Inc. 
IND 72,807
IND Sponsor: Matinas BioPharma Nanotechnologies, Inc. 
1545 Route 206 South, Suite 302
Bedminster, NJ 07921
Phone: 908-443-1860
Email: info@matinasbiopharma.com
Medical Monitor: Haran Schlamm, MD
Matinas BioPharma Nanotechnologies, Inc.
1545 Route 206 South, Suite 302 
Bedminster NJ 07921
Phone: (917) 859-4587
Email: hschlamm@matinasbiopharma.com


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Table of Contents
Table of Contents........................................................................................................3
Statement of Compliance.............................................................................................8
List of Abbreviations ....................................................................................................8
Protocol Summary ...................................................................................................11
Précis
....................................................................................................................14
1
Background Information and Scientific Rationale .............................................15
1.1
Background Information..............................................................................15
1.1.1
Description of the Study Agent ......................................................................15
1.1.2
Summary of Previous Preclinical Studies ....................................................16
1.1.3
Summary of Relevant Clinical Studies.........................................................18
1.2
Rationale .....................................................................................................19
2
Study Objectives ..........................................................................................20
2.1
Primary Objective .........................................................................................20
2.2
Secondary Objectives...................................................................................20
2.3
Exploratory Objective....................................................................................20
3
Study Design...............................................................................................21
3.1
Description of the Study Design...................................................................21
3.2
Study Endpoints..........................................................................................23
3.2.1
Primary Endpoint.........................................................................................23
3.2.2
Secondary Endpoints..................................................................................24
3.2.3
Exploratory Endpoints.................................................................................25
4
Study Population.........................................................................................25
4.1
Rationale for Subject Selection......................................................................25
4.2
Patient Inclusion Criteria ...............................................................................26
4.3
Patient Exclusion Criteria ..............................................................................27
Co-enrollment Guidelines:....................................................................................28
4.4
Justification for Exclusion of Special Populations..........................................28
Exclusion of Women.............................................................................................28
Exclusion of Children............................................................................................28
Exclusion of Adults Lacking Capacity to Provide Consent...................................29
5
Study Agent/Interventions ...............................................................................29
5.1
Disposition and Dispensation ...........................................................................29
5.1.1 Study Drug Packaging and Labeling............................................................29
5.2
Study Agent Storage andStability..................................................................30
5.2.1 Study Drug Storage ......................................................................................30
5.3
Description, Preparation, and Administration of Study Drug Product .....................30
5.3.1
Description...................................................................................................30
5.3.2
Dose Adjustments/Modifications/Delays.....................................................31
5.3.3
Duration of Therapy ....................................................................................31
5.3.4
Tracking of Dose .........................................................................................31
5.3.5
Limitations on Prior Therapy........................................................................32
5.4
Study Product Accountability Procedures ....................................................32
5.5
Concomitant Medications and Procedures ..................................................32


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5.6
Drug Interactions.........................................................................................32
Antineoplastic Agents.............................................................................................33
Corticosteroids and Corticotropin.........................................................................33
Digitalis Glycosides................................................................................................33
Flucytosine ............................................................................................................33
Azoles...................................................................................................................33
Leukocyte Transfusions .........................................................................................33
Other Nephrotoxic Medications ..............................................................................33
5.7
Prohibited Medications and Procedures ......................................................34
6
Study Schedule...........................................................................................34
6.1
Screening....................................................................................................34
6.2
Baseline.......................................................................................................35
6.3
Treatment at 200 mg/day ..............................................................................35
6.4
Dose Escalation to 400 mg/day .....................................................................37
6.5
Dose Escalation to 800 mg/day .....................................................................39
6.6
Extension of StudyDrug..............................................................................40
6.7
Early Termination Visit ..................................................................................43
7
Study Procedures/Evaluations ....................................................................43
7.1
Clinical Evaluations ......................................................................................43
Clinical Response Oropharyngeal/Esophageal Candidiasis: ...............................43
Clinical Response Vulvovaginal Candidiasis:.......................................................44
Clinical Response OMC: ......................................................................................44
7.2
Endoscopic Evaluations..............................................................................44
7.3
Mycological Evaluations ...............................................................................45
7.4
Laboratory Evaluations ...............................................................................45
Stool, Saliva, and Vaginal Secretions ......................................................................45
Urine ....................................................................................................................46
Serum/Urine Pregnancy Test .................................................................................46
Blood Draws.........................................................................................................46
8
Potential Risks and Benefits ..........................................................................47
8.1
Potential Risks .............................................................................................47
8.2
Potential Benefits .........................................................................................50
9
Research Use of Stored Human Samples, Specimens, or Data............................50
10
Remuneration Plan for Subjects ....................................................................53
11
Assessment of Safety ...................................................................................53
11.1
Toxicity Scale...............................................................................................53
11.2
Recording/Documentation ..........................................................................53
11.3
Reporting Procedures.................................................................................55
11.3.1 Reporting to the NIH IRB..............................................................................55
11.3.2 Reporting to the NIAID Clinical Director ........................................................55
11.3.3 Specific Adverse Event Reporting Requirements to the Sponsor ......................55
Serious Adverse Event (SAE)................................................................................55
11.4
Pregnancy...................................................................................................58
11.5
Type and Duration of the Follow-up of Subjects after Adverse Events...................59


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11.6
Pausing Rules for an Individual Subject .......................................................59
11.7
Stopping Rules for an Individual Subject ......................................................60
11.8
Halting Rules for the Protocol ........................................................................60
11.9
Withdrawal Criteria for an Individual Subject ...................................................61
11.10
Safety Oversight...........................................................................................61
11.10.1
Safety Monitoring Committee ..............................................................61
12
Clinical Monitoring Structure..........................................................................63
12.1
Site Monitoring Plan......................................................................................63
12.2
Auditing Procedures....................................................................................64
13
Statistical Considerations..............................................................................64
13.1
Study Hypotheses.......................................................................................64
13.2
Sample Size Justification ..............................................................................64
Analysis Populations ................................................................................................65
13.3
Description of the Analyses...........................................................................65
13.3.1 Efficacy Statistical Analysis...........................................................................65
13.3.2 Safety Analysis.............................................................................................65
13.3.3 PK Analysis.................................................................................................66
14
Ethics/Protection of Human Subjects ............................................................67
14.1
Informed Consent Process..........................................................................67
14.1.1 Remote Consent Process...........................................................................68
14.2
Subject Confidentiality ..................................................................................70
15
Data Handling and Record Keeping ...............................................................71
15.1
Data Capture and Management.....................................................................71
15.2
Record Retention .........................................................................................71
16
Scientific References....................................................................................72
Appendix A Toxicity Table .......................................................................................62
Appendix B Schedule of Procedures/Evaluations....................................................73
Appendix C Blood Volumes for Specimen Collection ..............................................75
Appendix D Schedule of Procedures/Evaluations – Extension Study ...............................76
Appendix E Blood Volumes for Specimen Collection – Extension Study ................78
Appendix F NIH SOP 801........................................................................................83
Appendix G NIH SOP 802 .......................................................................................93


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Statement of Compliance
The trial will be carried out in accordance with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) and the following: 
•
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812) 
NIH-funded investigators and clinical trial site staff who are responsible for the conduct, 
management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of 
both the protocol and the consent form must be obtained before any participant is enrolled.  
Any amendment to the protocol will require review and approval by the IRB before the 
changes are implemented to the study.  In addition, all changes to the consent form will be 
IRB-approved; an IRB determination will be made regarding whether a new consent needs to 
be obtained from participants who provided consent, using a previously approved consent 
form.
List of Abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
AMB
Amphotericin B
APECED
Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal 
Dystrophy
AST
Aspartate Transaminase
AUC
Area Under the Concentration vs. Time Curve
AUC0-24
Area Under the Concentration vs. Time Curve from Time Zero 
to 24 Hours Postdose
BID
Twice Daily
CAMB
Cochleate Oral Amphotericin B
CFR
Code Of Federal Regulations
Cmax
Maximum Plasma Concentration
CMC
Chronic Mucocutaneous Candidiasis
CRF
Case Report Form
CRP
C-Reactive Protein
CRIMSON
Clinical Research Information Management System of the 
NIAID
DAMB
Deoxycholate Solubilized Amphotericin B
DCR
Division of Clinical Research


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DSMB
Data and Safety Monitoring Board
EC
Esophageal Candidiasis
ESR
Erythrocyte Sedimentation Rate
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GI
Gastrointestinal
HRPP
Human Research Protection Program
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IND
Investigational New Drug
IP
Intraperitoneal
IRB
Institutional Review Board
IUD
Intrauterine Device
LCIM
Laboratory of Clinical Immunology and Microbiology
LC/MS-MS
Liquid Chromatography with Tandem Mass Spectrometry
MedRA
Medical Dictionary for Regulatory Activities
MFC
Minimum Fungicidal Concentration
NIAID
National Institute of Allergy and Infectious Diseases
NIH
National Institutes of Health
OCRPRO
Office of Clinical Research Policy and Regulatory Operations
OHRP
Office for Human Research Protections
OMC
Onychomycosis
OPC
Oropharyngeal Candidiasis
PBMC
Peripheral blood mononuclear cell
PI
Principal Investigator
PK
Pharmacokinetic(s)
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
SAE
Serious Adverse Event/Serious Adverse Experience
SD
Standard Deviation
SMC
Safety Monitoring Committee
SOC
System Organ Class
SOP
Standard Operation Procedure
T1/2
Elimination half-life
Tmax
Time to Reach Maximum Plasma Concentration
UP
Unanticipated Problem
VVC
Vulvovaginal Candidiasis
λZ
Apparent Elimination Rate Constant


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Protocol Summary
Full Title:
A Phase IIa Efficacy, Safety, Tolerability and 
Pharmacokinetic Study of Encochleated Amphotericin 
B (CAMB) in Patients with Mucocutaneous 
(Esophogeal, Oropharyngeal, Vulvovaginal) 
Candidiasis Who are Refractory or Intolerant to 
Standard Non-Intravenous Therapies
Short Title:
CAMB for CMC
ClinicalPhase:
IIa
IND Sponsor:
Matinas BioPharma Nanotechnologies, Inc.
Conducted by:
NIAID/LCIM
Principal Investigator:
Alexandra Freeman, MD
Sample Size:
N = 16
Accrual Ceiling:
20
Study Population:
Patients aged 18 to 75 years with mucocutaneous
candidiasis (esophageal, oropharyngeal, or 
vulvovaginal) who are refractory or intolerant to 
standard non-intravenous therapies. Pregnant 
patients will be excluded.
Accrual Period:
Closed to Enrollment
Study Design:
This is an open-label, dose-titration trial to study the
efficacy, safety, and pharmacokinetics of oral 
cochleate amphotericin B (CAMB) in the treatment of 
mucocutaneous candidiasis infections in patients who 
are refractory or intolerant to standard
non-intravenous therapies.
Study Duration:
60 months. Individual patient participation will last for
1-2 months, with the possibility for continuation of up 
to 60 months.
Study Agent:
CAMB
Intervention Description: CAMB will be administered orally at 200 mg/day
(100 mg BID). If there is a clinical response after


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2 weeks, then treatment will be extended for 2 more 
weeks. If there is no clinical response but study drug 
is tolerated, then doses will be escalated to
400 mg/day (200 mg BID). If after escalation there is  
a clinical response after 2 weeks, then treatment will 
be extended for 2 more weeks. If there is no clinical 
response and study drug is tolerated, then dose can 
be escalated again to 800 mg/day (400 mg BID) for 
an additional 2 weeks. If there is no clinical response 
after 2 weeks, the study drug will be discontinued. If 
there is clinical response after two weeks treatment 
will be extended for 2 more weeks. Participants have 
the option to enroll in the Extension phase of the 
study after achieving clinical response after 2 weeks 
at the highest tolerated dose of study drug.
Primary Objective:
To assess the clinical response to treatment of
mucocutaneous candidiasis (oropharyngeal 
candidiasis (OPC), esophageal candidiasis (EC), 
vulvovaginal candidiasis (VVC)) infections in patients 
who are refractory or intolerant to standard
non-intravenous therapies after treatment for 14-days 
with the highest titrated dosage (Target Dosage) of 
CAMB per patient.
Secondary Objectives:
1. To assess the plasma, urine, and salivary PK of
AMB after a single dose and after multiple doses 
(14 days) for both the starting dosage and 
subsequent up-titrations
2. To assess the safety and tolerability of CAMB in 
OPC, EC, and VVC
3. To assess mycological response in OPC, EC, and 
VVC
Exploratory Objective:
1. To assess the stool and vaginal secretion PK of
AMB after a single dose and after multiple doses 
(14 days) for both the starting dosage and 
subsequent up-titrations.
2. To assess clinical response in those patients with a 
concomitant diagnosis of OMC.
3. To assess the safety and efficacy of long-term 
treatment (up to 60 months) with CAMB.


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Primary Endpoints:
Percentage of patients with a primary diagnosis of
OPC, EC, or VVC who achieve Clinical Responder 
status after 14 days of treatment at the highest titrated 
CAMB dosage per patient (Target Dosage).
Secondary Endpoints:
1. Plasma, urine, and salivary single-dose and
steady-state PK parameters and disposition of oral 
CAMB
2. Dose linearity/proportionality of oral CAMB 
with titration
3. Clinical Responder status after 28 days at the 
Target Dosage
4. Clinical Responder status after 14 days at each 
dosage level
5. Mycological response after treatment for 14 days 
and 28 days with the Target Dosage
6. Mycological response after treatment with each 
dosage level for 14 days
7. Rate of treatment-limiting toxicity
8. Rate of clinical relapse
9. Incidence of nephrotoxicity
10. Incidence of hypokalemia
11. Incidence of adverse events (AEs)
12. Clinical Responder status after 14 days of 
treatment at the Target Dosage per patient of a 
secondary, less severe candida infection
Exploratory Endpoints:
1. Stool and vaginal secretion single-dose and
steady-state PK parameters and disposition of oral 
CAMB.
2. Clinical response in those patients with a 
concomitant diagnosis of OMC.
3. Long-term (up to 60 months) safety and efficacy.


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Précis
Current therapeutic options for mucocutaneous candidiasis infections are limited. 
Azole antifungals are available in oral formulations and are typically well  
tolerated, but resistance can develop, and toxicities that occur with prolonged   
use include hepatotoxicity, fluoride toxicity, and photosensitivity (with 
voriconazole). Echinocandins (eg, caspofungin and micafungin) are very well 
tolerated but are only available as intravenous formulations and resistance has 
developed. Amphotericin derivatives are used for their broad fungicidal activity, 
but they require parenteral administration and have significant side effects such 
as nephrotoxicity that worsens with longer courses of treatment. Amphotericin 
administered as an oral solution is not widely available, is not very effective, and 
irritates the oral and esophageal tissues.
Our clinical group currently follows many patients with mucocutaneous 
candidiasis, some of whom have become resistant or intolerant to oral or 
standard treatment. We plan to treat these individuals with cochleated oral 
amphotericin B (CAMB) in order to clear their infections. We will monitor for 
safety and pharmacokinetics of CAMB and will follow markers of treatment 
response of fungal infection.


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1
Background Information and Scientific Rationale
1.1
Background Information
1.1.1
Description of the Study Agent
Cochleate oral amphotericin B (CAMB) is a lipid-crystal, nano-particle formulation 
designed for targeted oral delivery of the antifungal drug amphotericin B (AMB). 
CAMB is a spiral-shaped phospholipid-cation precipitate that is primarily made up 
of phosphatidylserine — a naturally occurring phospholipid with a designation of 
generally recognized as safe (GRAS) from the FDA — and calcium. These 
multilayer cochleates are comprised of a solid lipid bilayer sheet, rolled into a 
spiral, with no internal aqueous space. This structure provides protection against 
degradation, which allows the inner structure to remain  intact even  after 
exposure to unfavorable environments (eg, low pH in the stomach), whilst 
providing the systemic delivery of AMB.
Historically, AMB has been considered the “gold standard” in antifungal 
treatments due to its broad spectrum of activity and lack of emergence of 
resistance. However, the use of AMB and its derivatives is limited by side effects, 
including nephrotoxicity, anemia and infusion related reactions. AMB disrupts the 
fungal cell wall via its high-affinity binding to ergosterol. The transmembrane 
channels that form as a result of this binding cause potassium to leak from the 
cell, thus initiating a lipid peroxidation cascade that causes irreversible damage   
to the cell.
CAMB demonstrates antifungal activity when administered orally. The efficacy is 
comparable to AMB but demonstrates reduced toxicity in animal models.
The sponsor changed the concentration of the study drug to a more concentrated 
formulation of 20mg/ml from the original concentration of 5mg/ml after 
participants in this study were on the extension phase.  A  27.5 mg/mL 
concentration has been tested in a study of CAMB in Cryptococcal meningitis in 
37 individuals and found to be well tolerated up to doses of  2.0grams daily. Due 
to viscosity concerns, however, the concentration was then changed to 20mg/ml.  
The dosing change has been submitted to the FDA and no concerns were 
reported.  
 After  May 2020, the company will  cease production of the 5mg/mL 


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concentration and move to  the higher concentration of  20mg/mL.
The transition to the 20mg/ml concentrate will be implemented once the 5mg/ml 
study drug supply is dispensed and fully used by the subjects in the trial.
1.1.2
Summary of Previous Preclinical Studies
Oral delivery of AMB formulated as CAMB was evaluated by measuring the 
concentration of AMB in liver, kidney, and lung of Candida albicans-infected mice 
for 14 days.1 Two groups of 10 mice were infected with C. albicans on Day 0.
Beginning on Day 1, the mice were treated with either the oral CAMB formulation 
(10 mg/kg) or intraperitoneal (IP) deoxycholate solubilized AMB (DAMB 
[Fungizone®], 2 mg/kg). Mice from each group were euthanized at 4 hours 
postdose, and tissue and plasma samples were recovered on Days 1, 3, 5, 7, 11,
and 15. The AMB levels in these samples were determined by reverse-phase 
high performance liquid chromatography. The tissue AMB levels for the orally 
dosed CAMB formulation ranged from 0.24 to 2.4 μg/g tissue throughout the 
treatment period. In vitro fungicidal activity measurements of AMB against
C. albicans have indicated a minimum fungicidal concentration (MFC) at or below 
these levels. Thus, the AMB tissue levels observed in this study were clearly 
sufficient for antifungal efficacy. In contrast to the tissue levels, AMB plasma  
levels for the mice treated with the oral CAMB formulation were typically below
0.08 μg/mL. Despite relatively low plasma concentration, the orally administered 
CAMB appeared to be effectively transported to the tissues. It is possible that 
immune system phagocytes directly delivered CAMB to the sites of infection.
In another study of AMB protection against candidiasis infection in mice, infected 
animals were treated orally with AmBisome® (10 mg/kg) or CAMB (0.5, 2.5, 5.0, 
10, or 20 mg/kg), or IP with DAMB (1.0 or 2.0 mg/kg).2 Treatment with DAMB 
resulted in a 70% and 100% survival for the 1.0 and 2.0 mg/kg doses, 
respectively. Oral AmBisome at 10 mg/kg resulted in 90% survival. The
CAMB-treated animals showed a 100% survival rate at all doses.
A mouse model was also used to compare the antifungal activities of CAMB and 
DAMB in treating mice with two levels of immunosuppression induced by 
cyclophosphamide therapy with Aspergillus infection. Oral administration of 
CAMB at 10 mg/kg per day for 10 days was protective against Aspergillus 


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infection, which was comparable to the protective effect of IP administered   
DAMB at 4 mg/kg per day (adjusted from average human dosage) after 10 days. 
Less immunosuppressed mice demonstrated a dose-dependent reduction in 
fungal tissue burden for all target organs. Fungal load in the liver and lung of  
mice orally treated with CAMB at 5 mg/kg/day was equivalent to the organ fungal 
load in mice IP treated with 4-mg/kg DAMB. However, treatment with CAMB at  
20 mg/kg/day was required for maximum reduction of fungal load in the kidneys.
In the more immunosuppressed mice, oral administration of CAMB  at
40 mg/kg/day resulted in a 90% survival rate in infected mice after 4 days, and a 
70% survival rate on Day 14. This was compared to DAMB at 4 mg/kg/day, which 
offered only moderate protection. CAMB at 20 mg/kg/day produced a
70% survival rate after 4 days, and a 60% survival rate on Day 14. A 2-log to
3-log reduction in CFU/g of tissue was observed at CAMB doses ≥10 mg/kg/day,
and Aspergillus was almost undetectable at doses above 20 mg/kg/day. Lower 
doses did prevent the spread of Aspergillus infection, but had less than
50% survival rates by Day 5.
This study also demonstrated that repeated oral administrations of CAMB are 
effective for tissue distribution, as was shown by the tissue-to-blood partition 
coefficient pattern that was similar to the organ distribution pattern, which 
indicates predictable penetration of the drug to target organ tissues.
Nephrotoxicity was tested and shown to be significantly reduced in mice treated 
with CAMB compared to mice treated with DAMB.
A separate study using a rat and a dog model tested the toxicokinetic effect of 
oral administration of CAMB.3 In this study, single daily doses were administered 
for 28 days. Dogs were dosed at 15, 30, or 45 mg/kg, and rats were dosed at 30, 
45, or 90 mg/kg. In both models, CAMB was well tolerated at all doses with no 
mortalities or clinical abnormalities.
In dogs, AMB was detected at all 3 doses in the kidney, liver, and spleen, but 
was not detected in the lung. In rats, AMB was detected in the kidney and liver 
but not the spleen.
There were no major sex-related differences in plasma toxicokinetics of AMB. 
Accumulation of AMB was observed as a result of repeated single daily dosing, 
but no toxic effects were observed.


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Overall, treatment with CAMB resulted in equal efficacy and reduced 
nephrotoxicity relative to treatment with DAMB.
1.1.3
Summary of Relevant Clinical Studies
In a Phase I study, using the drug concentration of 5mg/ml, subjects received a 
single dose of CAMB at 200 mg (approximately 3.3 mg/kg), 400 mg 
(approximately 6.7 mg/kg), or 800 mg (approximately 13.3 mg/kg). 
Pharmacokinetics (PK) was evaluated  through  96 hours postdose, and safety 
was evaluated for 2 weeks after administration.
CAMB was well tolerated at 200 and 400 mg. Subjects recorded some mild 
gastrointestinal distress and nausea. There were no abnormalities in kidney 
function or other safety laboratories noted. The clinical observations were similar 
to what was observed in the animal toxicology studies.4 Blood concentrations of
CAMB peaked around 10 to 12 hours postdose and were undetectable by 
48 hours postdose.
The 800-mg dose was not well tolerated, but there were no major adverse events 
(AEs). Increased nausea and gastrointestinal distress were observed, perhaps 
because the dose volume was high (160 mL). It appeared that 400 mg would be   
a proper upper limit for dosing, balancing efficacy, safety, and tolerability.
Increasing the frequency of dosing might allow higher daily dosing. In order to 
improve the tolerability this study will use twice daily (BID) dosing. Though this 
study will include the potential to titrate up to a total daily dosage of 800 mg. The 
highest individual dose that will be used in this study will be 400 mg (80 mL).
The study drug was changed from a concentration of 5mg/ml to 27.5mg/mL for a 
study in Uganda addressing safety and efficacy in the treatment of Cryptococcal 
meningitis.  Thirty-seven subjects were dosed with the 27.5mg/ml concentration, 
with a dose escalation up to 1.5g daily, with all participants tolerating the full 
dose, and no serious or unexpected adverse events. With a dose escalation up 
to 2.0g  daily, 8 of 9 participants tolerated the study drug.  One participant had 
grade 3 thrombocytopenia, that was not thought to be related to the study drug.  
Five of 9 participants had mild grade 1 GI side effects.   


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1.2
Rationale
As a result of the development of drug resistance, the current therapeutic options 
for mucocutaneous candidiasis are not as effective as they once were. Azole 
antifungals are available in oral formulations and typically well tolerated, but 
resistance can develop and toxicities occur, especially with prolonged use, 
including hepatotoxicity, fluoride toxicity, and photosensitivity (with voriconazole). 
Echinocandins (eg, caspofungin and micafungin) are very well tolerated but are 
only available as intravenous formulations and resistance can develop. AMB 
derivatives are used for their broad fungicidal activity, but they require parenteral 
administration and have significant side effects, such as nephrotoxicity, which 
worsens with longer courses of treatment. AMB administered as an oral solution  
is not widely available, is not very effective, and is irritating to the oral and 
esophageal tissues.
Our clinical group currently follows many patients with mucocutaneous 
candidiasis, some of whom have become refractory to standard or tolerated 
non-intravenous therapies. The majority of these patients have underlying
immune deficiencies disrupting the Th17 lymphocyte/IL-17/IL-22 pathway, which 
leads to abnormalities in host control of mucocutaneous candidiasis. Examples 
include STAT3 deficient Hyper IgE syndrome, gain of function STAT1 defects, 
autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED),
and IL-17/IL-22 autoantibodies from thymoma.
CAMB is a fungicidal, orally administered agent with a novel mechanism of 
absorption and distribution to infected tissues. Mouse studies have indicated that 
CAMB is well tolerated and is effective in eliminating Candida species infections 
and prolonging animal survival. Mouse and dog studies have also indicated lower 
toxicity for CAMB relative to its predecessor, intravenous DAMB. These animal 
studies also demonstrated the ability of CAMB to reach target organs efficiently, 
with quantifiable concentrations. A phase I trial in healthy volunteers reported no 
serious or dose-related AEs, with side effects being reported as mild nausea or 
mild gastrointestinal distress. Doses of 200 and 400 mg resulted in only mild AEs 
and no abnormal clinical or laboratory findings. A dose of 800 mg was also 
tolerated except for gastrointestinal (GI) symptoms which may have been related 
to the large volume (160 mL).


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The ability to provide amphotericin B as an oral formulation as CAMB may offer a 
new and promising alternative for patients with mucocutaneous candidiasis 
refractory to tolerated available therapies.
2
Study Objectives
2.1
Primary Objective
The primary objective is to assess the clinical response to treatment of 
mucocutaneous candidiasis (OPC, EC, VVC) infections in patients who are 
refractory or intolerant to standard non-intravenous therapies after treatment for 
14-days with the highest titrated dosage (Target Dosage) of CAMB per patient.
2.2
Secondary Objectives
•
To assess the plasma, urine, and salivary PK of CAMB after a single dose 
and after multiple doses (14 days) for both the starting dosage and 
subsequent up-titrations.
•
To assess the safety and tolerability of CAMB in OPC, EC, and VVC
•
To assess mycological response in OPC, EC, and VVC
•
2.3
Exploratory Objective
•
To assess the stool and vaginal secretion PK of CAMB after a single dose 
and after multiple doses (14 days) for both the starting dosage and 
subsequent up-titrations
•
To assess clinical response in those patients with a concomitant diagnosis 
of OMC.
•
To assess long-term (up to 60 months) safety and efficacy in those 
patients that qualify for extension (See Section 6.6).


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3
Study Design
3.1
Description of the Study Design
This is an open-label, dose-titration study that will assess the efficacy, safety, 
tolerability, and PK of CAMB in patients with mucocutaneous candidiasis (OPC, 
EC, or VVC) who are refractory or intolerant to standard non-intravenous 
therapies. We plan to enroll 16 patients. Patients will be recruited largely from 
cohorts followed on NIAID protocols with the following underlying diseases: 
STAT3 deficient Hyper IgE syndrome, gain of function STAT1 mutations, 
APECED, and thymoma with auto-antibodies with IL-17/IL-22 pathway. These 
underlying diagnoses predispose patients to chronic mucocutaneous candidiasis 
through disruption of similar pathways, thus suggesting that the patients may 
have similar benefits to this study drug. However, if there are patients that do not 
have these underlying diseases but fit the inclusion and exclusion criteria, the 
patient may be enrolled at the investigator’s discretion.
Days 27 to 54
Dosage 3 Phase
800 mg/day
Days 14-26
Dosage 2 Phase
400 mg/day
Days 27-41
Dosage 2 
Continuation 
400 mg/day
Days -14 to -1
Screening
Days 1-13
Dosage 1 Phase
200 mg/day
Days 14-28
Dosage 1 
Continuation 
200 mg/day


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dose escalation. Samples will also be collected on the morning of the final study visit for trough pharmacokinetics analysis.
2.
Patients with esophageal candidiasis will be encouraged to undergo an optional endoscopy at the end of treatment or within 4 
weeks of clinical improvement.
The study will include 14-day clinical evaluation periods. At the end of each 
dosing period, the investigator will make a determination to continue dosing the 
patient an additional 14 days with the same dosage or to escalate the dosage up 
to two times for an additional 14 days each time. The dosing phases are 
described below:
•
200 mg/day. On Day 1, patients will receive a single 100-mg dose of 
CAMB. Blood, urine, saliva, stool (optional), and vaginal secretions 
(optional) will be collected over the next 24 hours for PK analysis. 
Starting on Day 2, patients will receive 200 mg/day (100 mg BID) until 
Day 14. Study visits will be on Days 4 and 7. If on Day 14 the patient is 
determined to be a clinical responder and the drug is well tolerated, 
then they will receive a single 100-mg dose in the morning and blood, 
urine, saliva, stool (optional), and vaginal secretions (optional) will be 
collected over the next 24 hours for PK analysis. These patients will 
continue to receive 200 mg/day (100 mg BID) for the next 14 days. 
They will have a study visit on Days 21 and 28, and a final post 
treatment visit on Day 42.
•
400 mg/day. If on Day 14 the patient is determined to not be a clinical 
responder but the drug is well tolerated, then they will receive a single 
200-mg dose in the morning. Blood, urine, saliva, stool (optional), and 
vaginal secretions (optional) will be collected over the next 24 hours for 
PK analysis. These patients will receive 400 mg/day (200 mg BID) for
the next 14 days. They will have study visits on Days 17, 20, and 27. If 
on Day 27 they are determined to be a clinical responder and the drug 
is well tolerated, then they will receive a single 200-mg dose in the 
morning and blood, urine, saliva, stool (optional), and vaginal 
secretions (optional) will be collected over the next 24 hours for PK 
analysis. These patients will continue to receive 400 mg/day (200 mg 
BID) for the next 14 days. They will have a study visit on Days 34 and 
41, and a final post treatment visit on Day 55.
•
800 mg/day. If on Day 27 the patient is determined to not be a clinical 
responder but the drug is well tolerated, then they will receive a single 
400-mg dose in the morning. Blood, urine, saliva, stool (optional), and 
vaginal secretions (optional) will be collected over the next 24 hours for 


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PK analysis. These patients will receive 800 mg/day (400 mg BID) for 
the next 14 days. They will have study visits on Days 30, 33 and 40. If 
on Day 40 the patient is determined to not be a clinical responder, the 
study drug will be discontinued. At that point, follow-up procedures will 
be the same as an Early Termination Visit. If the patient is determined 
to be a clinical responder, the patient will continue to receive  
800mg/day (400mg BID) for the next 14 days.  They will have  
additional study visits on Days 47 and 54, and a final post treatment 
visit on Day 68.
•
A long-term extension of up to 60 months of study treatment will be 
offered for patients who respond clinically to therapy and have no 
safety or tolerability concerns (See Section 6.6).
3.2
Study Endpoints
3.2.1
Primary Endpoint
The primary endpoint is the percentage of patients with a primary diagnosis of 
OPC, EC, or VVC who achieve Clinical Responder status after 14 days of 
treatment at the highest titrated CAMB dosage per patient (Target Dosage).
Clinical Responder will be defined as patients who achieve Complete Clinical 
Cure or Clinical Improvement. The Clinical Response evaluation for each specific 
diagnosis of mucocutaneous candidiasis is described below:
OPC:
•
Clinical Cure: Absence of plaques or ulcers and absent or minimal 
symptoms.
•
Clinical Improvement: Partial resolution (≥ 50%) of pretreatment (Baseline) 
signs and symptoms.
•
Clinical Failure: No improvement (< 50%) or worsening of pretreatment 
(Baseline) signs or symptoms.
•
Not evaluable: Subject not evaluable due to lack of follow-up visits.
EC: Patients will undergo a research-indicated upper endoscopy to evaluate for 
esophageal candidiasis at the end of treatment or within 4 weeks of clinical 
improvement. Clinical cure will only be used for those patients who undergo this 


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endoscopy. If more than three patients decline to undergo this procedure, then 
this endpoint will be re-assessed.
•
Clinical Cure: Absence of plaques or ulcers on endoscopy and absent or 
minimal symptoms.
•
Clinical Improvement: Partial resolution (≥ 50%) of pretreatment (Baseline) 
symptoms or signs.
•
Clinical Failure: No improvement (< 50%) or worsening of pretreatment 
(Baseline) signs or symptoms.
•
Not evaluable: Subject not evaluable due to lack of follow-up visits.
VVC:
•
Clinical Cure: Absence of signs and symptoms of vaginitis.
•
Clinical Improvement: Reduction of ≥50% of the clinical severity score
from Baseline.
•
Clinical Failure: Worsening of symptoms or reduction in clinical score of
<50% from Baseline.
•
Not evaluable: Subject not evaluable due to lack of follow-up visits.
3.2.2
Secondary Endpoints
1. Plasma, urine, and salivary single-dose and steady-state PK parameters 
and disposition of oral CAMB.
2. Dose linearity/proportionality of oral CAMB with titration.
3. Clinical Responder status after 28 days at the Target Dosage.
4. Clinical Responder status after 14 days at each dosage level.
5. Mycological response after treatment for 14 days and 28 day with the 
Target Dosage.
6. Mycological response after treatment with each dosage level for 14 days.
7. Rate of treatment-limiting toxicity.
8. Rate of clinical relapse. Clinical relapse will be defined as a reoccurrence 
of clinical signs and symptoms after being sign and symptom free for
1 week.
9. Incidence of nephrotoxicity defined as an increase of more than 100% of 


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baseline serum creatinine.
10.Incidence of hypokalemia, defined as serum potassium ≤ 3 mmol/L during 
or within 3 weeks of completing treatment.
11.Incidence of AEs (see Section 11)
12.Clinical Responder status after 14 days of treatment at the Target Dosage 
per patient of a secondary, less severe candida infection. Clinical 
Responder will be defined as patients who achieve Complete Clinical Cure 
or Clinical Improvement.
3.2.3
Exploratory Endpoints
1. Stool and vaginal secretion single-dose and steady-state PK parameters 
and disposition of oral CAMB.
2. To assess clinical response in those patients with a concomitant diagnosis 
of OMC.
3. Long-term (up to 60 months) safety and efficacy response.
4
Study Population
4.1
Rationale for Subject Selection
We will enroll patients with immunodeficiencies that result in recurrent or chronic 
mucocutaneous candidiasis, who are refractory or intolerant to standard
non-intravenous therapies. The underlying diseases we expect these patients to
have include, but are not limited to: STAT3 deficient Hyper IgE syndrome, gain of 
function STAT1 mutations, APECED, and thymoma with autoantibodies with
IL-17/IL-22 pathway. If a patient has multiple Candida diagnoses, for example 
OPC and VVC or EC and VVC, the diagnosis that is more severe will be 
documented as the primary diagnosis and used in the primary endpoint analysis. 
However, all diagnoses will be evaluated and included in the secondary analysis.
Patients will be co-enrolled on 1 of the following NIAID protocols:
•
00-I-0159, Natural History, Management, and Genetics of the 
Hyperimmunoglobulin E Recurrent Infection Syndrome (HIES)
•
93-I-0119, Detection and Characterization of Host Defense Defects
•
07-I-0033, Screening Protocol for Detection and Characterization of 


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Infections and Infection Susceptibility
•
11-I-0187, The Natural History, Immunologic Correlates and Genetic 
Defects in Patients with Mucocutaneous and Invasive Fungal Infections
•
01-I-0202, Natural History, Genetics, Phenotype and Treatment of 
Mycobacterial Infections
We hope to enroll a minimum of 16 patients with OPC, EC, and/or VVC.
4.2
Patient Inclusion Criteria
•
Age 18-75 years
•
Patients must have a clinical diagnosis of at least one of the following:
•
Persistent OPC for greater than or equal to 5-days documented on 
at least one occasion by KOH or fungal stain and confirmed by 
mycological culture to be azole resistant within the previous 6 
months and/or intolerance to standard non-intravenous therapies or 
lack of improvement or worsening of OPC after receipt of 
appropriately dosed oral azole therapy.
•
EC associated with clinical symptoms of retrosternal pain, 
odynophagia, and/or pain with swallowing and documented by 
esophageal biopsy or visualization with culture documenting azole 
resistance within the previous 6 months and/or intolerance to 
standard non-intravenous therapies or lack of improvement or 
worsening of EC after appropriately dosed azole therapy.
•
Persistent VVC for greater than or equal to 5-days as documented 
by presence of vaginal symptoms and a positive wet mount  
showing Candida structures and confirmed by a vaginal culture 
positive for Candida with azole resistance within the previous 6 
months and/or intolerance to standard non-intravenous therapies or 
lack of improvement or worsening of VVC after receipt of 
appropriately dosed azole therapy.
•
Patient is expected to survive for ≥ 6 months.
•
Willing to have samples stored for future research.
•
Agree to use highly effective contraception (see below).
Contraception: Because the effects of CAMB on the developing human fetus 
are unknown, sexually active patients of childbearing potential must agree to 


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use highly effective contraception as outlined below before study entry and for 
the duration of study participation. Females of childbearing potential must have
a negative pregnancy test result before receiving CAMB. During the course of 
the study, if a patient becomes pregnant or suspects they are pregnant, then 
they should inform the study staff and their primary care physician 
immediately. Acceptable forms of contraception are:
•
Intrauterine device (IUD) or equivalent.
•
Hormonal contraceptives (eg, consistent, timely and continuous use of 
contraceptive pill, patch, ring, implant, or injection that has reached full 
efficacy prior to dosing). If the patient uses contraceptive pill, patch, or 
ring, then a barrier method (eg, male/female condom, cap, or 
diaphragm plus spermicide) must also be used at the time of  
potentially reproductive sexual activity.
•
Be in a stable, long-term monogamous relationship, per PI  
assessment, with a partner that does not pose any potential pregnancy 
risk, eg, has undergone a vasectomy at least 6 months prior to first 
dose of study agent or is of the same sex as the patient.
•
Have had a hysterectomy and/or a bilateral tubal ligation or both 
ovaries removed
4.3
Patient Exclusion Criteria
•
Allergy to any AMB product or any component of CAMB 
(eg, phosphatidylserine)
•
Have evidence of systemic fungal infections requiring intravenous 
antifungal therapy
•
Pregnant or nursing women, and women intending to become 
pregnant during the study period
•
Had a concomitant medical condition that could interfere with study 
drug evaluation or that is a contraindication to the proposed 
investigational treatment based upon known agent safety profile or 
toxicities.
•
Had any of the following laboratory abnormalities at the screening visit:
o
Alanine Transaminase (ALT), Aspartate Transaminase (AST) and 
Alkaline phosphatase (ALP) >2.5 times the upper limit of normal 
(ULN).


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o
Total bilirubin level > 2.5 times the ULN
o
Serum creatinine level > 2 times the ULN
o
Absolute neutrophil count less than 500 cells/µL
o
Potassium level <3.5 mmol/L
•
Exposure to any investigational agent within 4 weeks prior to Day 0 
(Baseline).
•
Current or recent history (past 12 months) of drug or alcohol abuse.
•
Use of intravenous AMB products within 1-week of start of study drug 
administration
•
Use of non-intravenous AMB products (such as oral AMB swishes) 
within 72 hours prior to start of study drug administration
•
Any other condition the investigator believes would interfere with the 
patient’s ability to provide informed consent, comply with study 
instructions, or which might confound the interpretation of the study 
results or put the subject at undue risk.
Co-enrollment Guidelines:
Co-enrollment in other trials is restricted, other than enrollment on observational 
studies. Consideration for co-enrollment in trials evaluating the use of a licensed 
medication will require the approval of Principal Investigator and Sponsor. Study
staff should be notified of co-enrollment as it may require the approval of primary 
investigator.
4.4
Justification for Exclusion of Special Populations
Exclusion of Women
•
Pregnancy: Pregnant women are excluded from this study because the 
effects of CAMB on the developing human fetus are unknown, and there is 
the potential for teratogenic or abortifacient effects.
•
Breastfeeding: Patients who are breastfeeding should cease when being 
treated with CAMB because of the potential risk for AEs in nursing infants.
Exclusion of Children
Children are not eligible for this study because this is an investigational study 
with very limited experience in humans regarding safety and appropriate dosing. 


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We hope that the results of this study will then allow further study including in 
pediatric patients.
Exclusion of Adults Lacking Capacity to Provide Consent
If participants permanently lose the ability to provide ongoing consent 
subsequent to giving initial consent, they will be withdrawn from the study 
(section 11.9). 
5
Study Agent/Interventions
5.1
Disposition and Dispensation
Study agent will be distributed via the NIH Pharmacy according to standard 
pharmacy procedures.
5.1.1
Study Drug Packaging and Labeling
The CAMB will be packaged into NalgeneTM amber PETG 125-mL square bottles 
with HDPE closures. The corresponding labels are:
Protocol: MB-70004
Subject ID:   
                               
Investigator Phone Number:
Encochleated Amphotericin B Suspension (CAMB) 
For Oral Use
5 mg/mL Amphotericin B
Lot#:  XXXXXXXX*
Contents:  XXX mL
Take as directed by Study Investigator 
Shake well before use.
Store refrigerated at 2-8° C. Protect from the light.
Caution: New Drug – Limited by Federal Law to Investigational Use. 
Matinas BioPharma Nanotechnologies, Inc. Bedminster, NJ
*Actual values will be listed on Study Drug label.
Patients will be supplied with measuring tools (eg, dispensing cups or syringes)  
to take home and use for study drug administration and will be instructed on how 


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to use them.
5.2
Study Agent Storage and Stability
5.2.1
Study Drug Storage
All study drug will be stored in a locked area. The area will be free of 
environmental extremes and with a limited access. Study drug will be kept 
refrigerated at 2°C to 8°C. The site will maintain records of storage temperature 
and make them available for Sponsor review.
Patients will be instructed to store study drug in a refrigerator at 2°C to 8°C 
(36°F-46°F). In order to travel with study drug, patients will be provided a cooler 
bag and freezer pack to maintain temperature.
5.3
Description, Preparation, and Administration of Study 
Drug Product
5.3.1
Description
CAMB is a yellow-to-orange suspension that is homogenous upon shaking. It 
should be stored between 2°C and 8°C. CAMB is light-sensitive and should be 
stored away from light.5 However, exposure of < 4 hours to fluorescent light and 
excursions of up to 24 hours at room temperature are acceptable. In this study, 
CAMB was initially provided at a concentration of 5 mg/mL and administered at 
up to 3 strengths: 100, 200, and 400 mg.
   After  May 31, 2020, the company has  ceased production of the 5mg/mL concentration and     
   move to  the higher concentrated formulation of  20mg/mL.                                                                           
   Preparation, Dosing and Administration
The study drug will be provided as an oral suspension. Patients will take the 
study drug twice per day to reach the total daily dose. Prior to administration, the 
study drug container will be shaken, the required quantity poured into a 
dispensing cup, and the remainder of the study drug returned to refrigerated 
storage. Patients with OPC and/or EC will be asked to swish the suspension in 
their mouths before swallowing and then refrain from eating or drinking for
30 minutes post-dose. Patients with VVC and/or OMC will be asked to drink 
suspension without swishing. CAMB is provided at a single concentration   


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(20 mg/mL). Patients will be instructed to dispense the appropriate volume 
of solution (5,10 or 20 mL) to reach the target dose, according to the 
following table:
Total Daily 
Dose 
(mg/day)
Single Dose 
(mg/dose)
Single Dose Volume, 
5mg/mL concentration 
(mL)
Single Dose 
Volume, 20mg/mL 
concentrations 
(mL)
200
100
20
5
400
200
40
10
800
400
80
20
5.3.2
Dose Adjustments/Modifications/Delays
If the GFR falls below 60 mL/min/1.73m2 or 30% lower than baseline then we will 
suspend treatment until GFR returns to baseline, in consultation with the safety 
monitoring committee.
For other toxicities thought to be the result of the study drug, including 
gastrointestinal symptoms, treatment will be suspended until the symptoms 
resolve. The investigator and patient will consider re-initiation on the basis of 
clinical findings and symptom severity.
5.3.3
Duration of Therapy
Subjects will take the study drug for 28 days at the clinically effective tolerated 
dosage (Target Dosage). However, if study drug is tolerated and the patient has 
clinical efficacy at two weeks, the extension phase of the protocol will be offered, 
in which the patient can continue the study drug for up to 60 months.
5.3.4
Tracking of Dose
Study drug bottles will be returned to assess adherence. Patient medication logs 
will also be used to aid with adherence.
5.3.5
Limitations on Prior Therapy
Subjects may continue other pre-existing chronic (> 2 weeks) antimicrobial 
therapies including azole antifungals. Intravenous amphotericin products will be 


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stopped at least 1 week before initiation of the study drug, and non-intravenous 
amphotericin products (such as oral AMB swishes) will be stopped at least
72 hours before initiation of the study. Other antimicrobial agents that are added 
during the course of the study need to be approved by one of the investigators.
5.4
Study Product Accountability Procedures
The dispensing pharmacy will acknowledge receipt of all shipments of 
investigational drug product and maintain accurate accountability records. The 
study drug administered to the subject will be documented in the medical record. 
All study drug will be stored and disposed of according to the manufacturer’s 
recommendations. At each monitoring visit and the conclusion of the study, an 
inventory of study drug will be performed by the Study Monitor (or designee) and 
the Investigator (or designee). Any missing supplies must be indicated on the 
drug accountability form along with an explanation of the discrepancy. The 
Investigator will be instructed to return all unused study drug to Aquarius or 
designee, and return a copy of the Clinical Supplies Return Form.
5.5
Concomitant Medications and Procedures
Medications to be reported in Clinical Research Information Management System 
of the NIAID (CRIMSON) are concomitant prescription medications, over-the- 
counter medications, and non-prescription medications taken at the time of AEs 
(all grades).
5.6
Drug Interactions
CAMB should be used with caution in patients receiving chemotherapy with 
certain agents, in patients receiving lymphocyte transfusions, or curare-class
paralytic agents. Concurrent use of CAMB with drugs that lower serum  
potassium requires monitoring of serum potassium levels. Other drugs that have 
increased risk in the presence of hypokalemia should be used with caution, 
including digitalis and neuromuscular blockade agents (paralytics). The following 
drugs are known to interact with AMB and may interact with CAMB:
Antineoplastic Agents
Concurrent use of antineoplastic agents may enhance the potential for renal 
toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given 


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concomitantly with caution.
Corticosteroids and Corticotropin
Concurrent use of corticosteroids and corticotropin may potentiate hypokalemia, 
which could predispose the patient to cardiac dysfunction. If used concomitantly 
with CAMB, then serum electrolytes and cardiac function should be closely 
monitored.
Digitalis Glycosides
Concurrent use may induce hypokalemia and may potentiate digitalis toxicity. 
When administered concomitantly, serum potassium levels should be closely 
monitored.
Flucytosine
Concurrent use of flucytosine may increase the toxicity of flucytosine by possibly 
increasing its cellular uptake and/or impairing its renal excretion.
Azoles
In vitro and in vivo animal studies of the combination of AMB and imidazoles 
suggest that imidazoles may induce fungal resistance to AMB. Combination 
therapy should be administered with caution, especially in immunocompromised 
patients.
Leukocyte Transfusions
Acute pulmonary toxicity has been reported in patients simultaneously receiving 
intravenous AMB and leukocyte transfusions.
Other Nephrotoxic Medications
Concurrent use of AMB and other nephrotoxic medications may enhance the 
potential for drug-induced renal toxicity. Intensive monitoring of renal function is 
recommended in patients requiring any combination of nephrotoxic medications.
AMB-induced hypokalemia may enhance the curariform effect of skeletal muscle 
relaxants (eg, tubocurarine) due to hypokalemia. When administered 
concomitantly, serum potassium levels should be closely monitored.
5.7
Prohibited Medications and Procedures
Concomitant treatment with all AMB products including liposomal formulations 
and oral AMB will not be permitted.


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Azole antifungals will be permitted if used for another indication besides 
treatment of Candida infection, such as for the treatment or prevention of mold 
infection.
6
Study Schedule
See Appendix B for tabulated schedule of procedures and evaluations. See 
Appendix C for volumes of blood to be collected at each visit. Study visits will 
take place at the NIH Clinical Center, with the exception of certain sample 
collections that may be done at a local laboratory as indicated below. Patients 
may be admitted to the Clinical Center as inpatients on the days that 24-hour PK 
samples are collected.
6.1
Screening
Enrolled patients will be followed on one of the NIAID protocols that allows 
treatment and evaluation of underlying immune defects, including protocols 
#00-I-0159, 93-I-0119, 07-I-0033, 11-I-0187, and 01-I-0202. The eligibility
criteria, including medical history and physical examination findings, will be 
evaluated from the immunologic, genetic, and/or initial infection work up 
conducted as part of the referring protocol. Laboratory, history, and exam  
findings to fulfill inclusion and exclusion criteria must be collected within 2 weeks 
prior to enrollment in this protocol (See Appendix B Schedule of 
Procedures/Evaluations). If findings are not available from the referring protocol 
within that timeframe, then physical exam, medical history, blood and urine 
collection, pregnancy test, and microbiology will be conducted under this 
protocol. Patients with signs and symptoms of esophageal candidiasis will have 
an upper endoscopy performed under this protocol within 4 weeks before study 
drug initiation to document the extent of disease and to allow for biopsy and/or
visualizing with culture swabs. Patients will sign an informed consent document 
before undergoing any research procedures under this protocol.
6.2
Baseline
On Study Day 0, patients will undergo the following procedures:
•
Medical/Medication history
•
Baseline clinical assessment of Candida infection


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•
Physical exam
•
Blood draw and urine collection (see section 7.4) if screening was more 
than 72 hours prior
•
Microbiology (fungal culture of affected site of Candida infection, see 
section 7.3), with the exception of esophageal cultures
•
Optional collection of peripheral blood mononuclear cells (PBMCs) for 
storage
•
Optional vaginal secretions collection
If the screening evaluations were conducted with 72 hours of the baseline visit, 
then blood draw, urine, and vaginal swab collection will not be repeated at 
baseline.
6.3
Treatment at 200 mg/day
On Study Day 1, patients will undergo clinical assessment and physical exam,  
and assessment of AEs and concomitant medications. Blood and urine will also  
be collected for additional laboratory evaluations (see Section 7.4). Patients who 
are capable of becoming pregnant will have a pregnancy test. Predose blood and 
saliva PK samples will be collected. Patients will then receive a single 100-mg 
dose of CAMB, followed by 24-hour PK sampling of blood., urine, saliva, stool 
(optional), and vaginal secretions (optional).
On Study Day 2, the 24-hour timepoint samples of blood , urine, saliva, stool 
(optional), and vaginal secretions (optional) will be collected. Patients will  
undergo assessment of AEs and concomitant medications. Blood will also be 
collected for additional laboratory evaluations. Patients will then begin 100-mg  
BID dosing for 14 days. Urinalysis for laboratory evaluation will be collected after 
the 24-hour urine PK concludes and can be collected after administering the 
morning dose of study drug.
On Study Day 4 (± 1 day), the following procedures and evaluations will be 
performed:
•
Clinical assessment and physical exam as needed to evaluate new 
symptoms/complaints
•
Assessment of AEs and concomitant medications
•
Blood draw and urine collection


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On Study Day 7 (± 1 day), the following procedures/evaluations will be 
performed:
•
Assessment of AEs and concomitant medications
•
Blood draw and urine collection
For this time point, the patient and the investigator have the option of doing a 
phone interview and obtaining the blood and urine lab work at a local laboratory. 
A copy of the results should be sent to the investigator.
On Study Day 14 (± 3 days), before administration of the morning dose, patients 
will undergo clinical assessment and physical exam with clinical response 
calculation, and assessment of AEs and concomitant medications. Patients who 
are capable of becoming pregnant will have a pregnancy test. If the patient is a 
Clinical Responder and the drug is well tolerated, then the dosage of 100 mg BID 
will be extended for 14 more days. The patient will only receive the morning dose 
on Day 14 and the following procedures/evaluations will be performed:
•
Blood draw and urine collection
•
Collection of 24-hour PK samples: Predose (0-hour timepoint) blood and 
saliva will be collected, followed by 24-hour PK sampling of blood., urine, 
saliva, stool (optional), and vaginal secretions (optional)
•
Plasma , urine, stool (optional), salivary, and vaginal secretions (optional) 
24-hour timepoint to be collected on Day 15.
•
Microbiology (fungal culture of affected site)
•
Optional collection of PBMCs for storage
On Study Day 21 (± 3 days), the following procedures/evaluations will be 
performed:
•
Assessment of AEs and concomitant medications
•
Blood draw and urine collection
For this time point, the patient and the investigator have the option of doing a 
phone interview and obtaining the blood and urine lab work at a local laboratory. 
A copy of the results should be sent to the investigator.
On Study Day 28 (± 3 days), the following procedures/evaluations will be 
performed:
•
Clinical assessment and physical exam


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•
Endoscopy with biopsies for EC patients (within 4 weeks of clinical 
improvement)
•
Assessment of AEs and concomitant medications
•
Blood draw and urine collection
•
Pregnancy testing
•
Trough plasma PK collection
•
Microbiology (fungal culture of affected sites)
•
Optional collection of PBMCs for storage
Study Day 42 (± 3 days) will be the post-treatment End of Study visit for patients 
who continued 200 mg/day. For this visit, the patient and the investigator have  
the option of doing the assessment over the telephone instead of making a  
clinical visit. In this instance the laboratory testing should be performed by a local 
laboratory and a copy of the results should be sent to the investigator. The 
following procedures/evaluations will be performed:
•
Assessment of AEs
•
Blood draw and urine collection
6.4
Dose Escalation to 400 mg/day
If on Day 14 the patient is determined to not be a Clinical Responder but the 
study drug is well tolerated, then the dosage will be increased to 400 mg/day. 
These patients will receive only the morning dose (200 mg) on Day 14. The 
following procedures will be performed:
•
Blood draw and urine collection
•
Pregnancy testing (result confirmed before administration of dose)
•
Collection of 24-hour PK samples: Predose (0-hour timepoint) blood and 
saliva will be collected, followed by 24-hour PK sampling of blood., urine, 
saliva, stool (optional), and vaginal secretions (optional)
•
Plasma , urine, stool (optional), salivary, and vaginal secretions (optional) 
24-hour timepoint to be collected on Day 15
•
Microbiology (fungal culture of affected site)
•
Optional collection of PBMCs for storage
Starting on Day 15, patients will be dosed with 400 mg/day (200 mg BID) for 
14 days. Prior to dosing, patients will undergo assessment of AEs and 
concomitant medications. Blood will also be collected for additional laboratory
evaluations. Patients will then begin 200-mg BID dosing for 14 days. Urinalysis 
for laboratory evaluation will be collected after the 24-hour urine PK concludes 


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and can be collected after administering the morning dose of study drug. Study 
visits will be on Days 17 (± 2 days), 20 (± 2 days), 27 (± 3 days), 34 (± 3 days), 
and 41 (± 3 days). Clinical assessment and physical exam, assessment of AEs 
and concomitant medications, blood draw, and urine collected will be conducted 
on Days 17, 27 and 41. As with the Day 7 visit, the evaluations for Day 20 can be 
conducted locally, with blood and urine collected from the patient’s local 
diagnostic laboratory.
On Day 27 before administration of the morning dose, patients will undergo 
clinical assessment and physical exam with clinical response calculation, and 
assessment of AEs and concomitant medications. Patients who are capable of 
becoming pregnant will have a pregnancy test. If the patient is a Clinical 
Responder and the drug is well tolerated, then the dosage of 200 mg BID will be 
extended for 14 more days. The patient will only receive the morning dose on 
Day 27. Patients will undergo blood draw for research testing and optional 
collection of PBMCs for storage, urine and fungal culture of the affected site.
Samples of blood , urine, saliva, stool (optional), and vaginal secretions (optional) 
for 24-hour PK analysis will also be conducted, the same as at Day 14.
As with the Days 7 and 20 visits, the visit for Day 34 can be conducted locally, 
with blood and urine collected from the patient’s local diagnostic laboratory.
On Study Day 41 (± 3 days) the following procedures/evaluations will be 
performed:
•
Clinical assessment and physical exam
•
Endoscopy with biopsies for EC patients (within 4 weeks of clinical 
improvement)
•
Assessment of AEs and concomitant medications
•
Blood draw and urine collection
•
Pregnancy testing
•
Trough plasma PK collection
•
Microbiology (fungal culture of affected sites)
•
Optional collection of PBMCs for storage
Study Day 55 (± 3 days) will be the post-treatment End of Study visit for patients 
who continued 400 mg/day. For this visit, the patient and the investigator have  
the option of having a phone assessment instead of making a clinical visit. In this 


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instance the laboratory testing should be performed by a local laboratory and a 
copy of the results should be sent to the investigator. The following 
procedures/evaluations will be performed:
•
Assessment of AEs
•
Blood draw and urine collection
6.5
Dose Escalation to 800 mg/day
If on Day 27 the patient is determined to not be a Clinical Responder but the 
study drug is well tolerated, then the dosage will be increased to 800 mg/day. 
These patients will receive only the morning dose (400 mg) on Day 27. The 
following procedures will be performed:
•
Blood draw and urine collection
•
Pregnancy testing (result confirmed before administration of dose)
•
Collection of 24-hour PK samples: Predose (0-hour timepoint) blood and 
saliva will be collected, followed by 24-hour PK sampling of blood, urine, 
saliva, stool (optional), and vaginal secretions (optional)
•
Plasma, urine, stool (optional), salivary, and vaginal secretions (optional) 
24-hour timepoint to be collected on Day 28
Microbiology (fungal culture of affected site)
•
Optional collection of PBMCs for storage
Starting on Day 28, patients will be dosed with 800 mg/day (400 mg BID) for 
14 days. Prior to dosing, patients will undergo assessment of AEs and 
concomitant medications. Blood will also be collected for additional laboratory
evaluations. Patients will then begin 400-mg BID dosing for 14 days. Urinalysis 
for laboratory evaluation will be collected after the 24-hour urine PK concludes 
and can be collected after administering the morning dose of study drug. Study 
visits will be on Days 30 (± 2 days), 33 (± 2 days), 40 (± 3 days), 47 (± 3 days), 
54 (± 3 days) and 68 ((± 3 days). Clinical assessment and physical exam,
assessment of AEs and concomitant medications, blood draw, and urine 
collected will be conducted on Days 30, 40, and 54. As with the Day 7 visit, the 
evaluations for Days 33 and 47 can be conducted locally, and blood and urine 
can be collected from the patient’s local diagnostic laboratory.
At the Day 40 Study Visit, patients will be assessed for clinical response to study 
drug. If the patient is determined to not be a clinical responder, the study drug  


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will be discontinued.  Follow-up will occur two weeks later (Day 54 +/- 3 days)  
and include all of the procedures performed at an Early Termination visit.
If the patient is a clinical responder, (s)he will only receive the morning dose on 
Day 40. Procedures will be the same as on Day 27.
On Study Day 54 (± 3 days), the following procedures/evaluations will be 
performed:
•
Clinical assessment and physical exam
•
Endoscopy with biopsies for EC patients (within 4 weeks of clinical 
improvement)
•
Assessment of AEs and concomitant medications
•
Blood draw and urine collection
•
Pregnancy testing
•
Trough plasma PK collection
•
Microbiology (fungal culture of affected sites)
•
Optional collection of PBMCs for storage
Study Day 68 (± 3 days) will be the post-treatment End of Study visit for patients 
who continued 800 mg/day. For this visit, the patient and the investigator have 
the option of doing the visit locally instead of making a clinical visit. In this 
instance the laboratory testing should be performed by a local laboratory and a 
copy of the results should be sent to the investigator. The following 
procedures/evaluations will be performed:
•
Assessment of AEs
•
Blood draw and urine collection
6.6
Extension of Study Drug
Many of the patients expected to enroll into this study have underlying 
immunodeficiencies that predispose them to chronic mucocutaneous candidiasis, 
and recurrence is highly likely when the study drug is stopped. Therefore, study 
participants who are tolerating the study medication and are clinical responders, 
will be permitted to enroll in a study extension. The extension may be continued 
from the end of the period of medication administration (i.e. the end of the 2 week 
period of study medication at the dose that allows efficacy and tolerance of drug) 
or the participant may have a break of study medication before re-starting the 
extension period. If there is a break between the initial study drug use and the 
extension phase, the subjects will be offered alternative antifungals, such as 


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topical amphotericin swish and spit, to help control the oral pharyngeal candida 
infection. Breaks in study drug extension will be minimized as much as possible. 
Any break through infections may be treated by either the Principle Investigator   
or the subject’s Primary Care Provider. In case of recurrence or worsening of the 
mucocutaneous candida infections while on the extension part of the study drug, 
despite excellent adherence, that requires new or additional antifungals, the 
Principal Investigator will stop the study drug.
Study drug will be continued at the minimum dose (100mg BID, 200mg BID, or 
400mg BID) meeting clinical responder criteria with good tolerance. The 
investigator will have the ability to change daily dosage and frequency of study 
drug based on patient response and tolerability between the range of 200 mg to 
800 mg per day.
Extension of study medication will be offered if the following criteria are met:
•
Clinical responder status for oral, esophageal or vaginal disease at the 
end of the 2 week study point at the highest tolerated dose to which they 
respond (Day 14 for 200 mg, Day 27 for 400 mg, or Day 40 for 800 mg).
•
The study participant does not have any of the laboratory criteria meeting 
the exclusion criteria
o
Alanine Transaminase (ALT), Aspartate Transaminase (AST) and 
Alkaline phosphatase (ALP) >2.5 times the upper limit of normal 
(ULN).
o
Total bilirubin level > 2.5 times the ULN
o
Serum creatinine level > 2 times the ULN
o
Absolute neutrophil count less than 500 cells/µL
o
Potassium level <3.5 mmol/L
•
Good tolerance of study drug
o
No gastrointestinal toxicity (nausea/vomiting/diarrhea) that is 
interfering with the ability to perform regular every day activities.
o
Less than two Grade 3 events and/or one Grade 4 event that are 
possibly, probably, or definitely related to participation in the trial;
o
No SAEs that are possibly, probably or definitely related to the 
study drug.
•
No laboratory abnormalities, intercurrent illness, other medical condition or 
situation that occurs such that continued participation in the study would  
not be in the best interest of the subject.


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Study medication will be allowed to continue for up to 60 months with the 
following monitoring:
•
Bi-weekly safety laboratories (or more frequently as per PI discretion) 
including CBC/diff, chemistry panels (hepatic, mineral and acute). These 
can be performed at the NIH clinical center or at the home laboratory. (+/- 
4 days)
•
Bi-weekly visits to the NIH clinical center (+/- 3 days) for the first 1 month 
and then the visits can be extended to every 12 weeks (+/- 7 days) unless 
clinically indicated to be more frequent. At these visits the following study 
procedures will be performed:
o
Clinical assessment and physical exam
o
Assessment of AEs and concomitant medications
o
Blood draw including CBC/diff, chemistry panels (hepatic, mineral 
and acute), and urinalysis.
o
Pregnancy testing (except week 2 NIH visit after start of extension 
phase)
o
Serum and PBMCs may be collected for storage
o
Urine, plasma, stool, saliva and vaginal secretions may be collected 
and stored
o
Microbiology (fungal culture of affected sites)
o
OMC Picture of affected areas every 8 weeks
If study participants are only seen every 12 weeks, they will be contacted by 
phone or NIH-approved video conference platform at the 2-week interim point 
to assess for AEs, concomitant medications, and drug compliance. The 
laboratory testing can be performed by a local laboratory and a copy of the 
results should be sent to the investigator. 
6.7
Early Termination Visit
All effort will be made to conduct an early termination visit for subjects who 
withdraw from the study. This visit will include all of the procedures performed at 
the normal end-of-study visit, with the exception of collection of plasma , urine, 
saliva, stool (optional), and vaginal secretion (optional) samples for PK analysis.


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7
Study Procedures/Evaluations
7.1
Clinical Evaluations
At each study visit that requires a clinical assessment per protocol, the 
investigator will examine the patient and document the clinical signs and 
symptoms according to the scales described below.
Clinical Response Oropharyngeal/Esophageal Candidiasis:
The investigator will examine the oral cavity and question the subject to identify 
any signs/symptoms of infection and categorize clinical response to treatment.
The presence of plaques will graded according to the following scale, modified 
from an AIDS Clinical Trial Group (ACTG) Protocol:
•
0 None = Absent
•
1 Minimal = 1-5 discrete plaques and/or one confluent plaque ≤ 3 cm in 
longest length
•
2 Diffuse = Plaques that are more than minimal extent; or presence of 
ulcers
•
3 Worse = Plaques were clearly worse than on previous visit
The severity symptoms (dysphagia, odynophagia, retrosternal pain, oral pain, 
burning of mouth) will be graded according to the following scale:
•
0 None = Symptom was not present.
•
1 Mild = Symptom was present, but no or minimal interference was noted 
with eating.
•
2 Moderate = Symptom(s) present and led to interference with eating 
many foods.
•
3 Severe = Symptom(s) were very marked. The subject was unable to eat 
most foods.
The sum of the symptom scores will be used as the severity score.


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Clinical Response Vulvovaginal Candidiasis:
The investigator will examine the patient and question the subject to identify any 
signs/symptoms of infection and categorize clinical response to treatment. The 
following signs and symptoms will be evaluated in each patient:
•
Vaginal erythema
•
Vulvovaginal pruritus
•
Vaginal discharge
The severity of each symptom will be graded according to the following scale:
•
0 = Absent
•
1 = Mild
•
2 = Moderate
•
3 = Severe
The sum of the scores for all symptoms will be used as the severity score.
Clinical Response OMC:
The investigator will assess the signs and symptoms of OMC. For clinical 
response, the target thumbnail or great toenail will be assessed for the presence, 
absence, or improvement of OMC and subungual hyperkeratosis, and  
percentage of nail involvement will be estimated. Pictures will be taken every 2- 
weeks to document changes. The pictures will be taken by a medical 
photographer and will not contain identifiable information. Patients will sign the 
standard NIH photography consent form before pictures are taken, and may 
decline photography.
7.2
Endoscopic Evaluations
Patients with a diagnosis of EC will undergo a clinically indicated endoscopic 
evaluation under either conscious sedation or general anesthesia within 4 weeks
before study drug initiation. These patients will also undergo a second 
endoscopy for research purposes only at end of treatment or within 4 weeks of 
clinical improvement, whichever occurs first. Each endoscopic evaluation will be 
graded according to the following scale:
•
0 None = Absent


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•
1 Minimal = 1 to 5 discrete plaques and/or one confluent plaque ≤ 3 cm in 
longest length
•
2 Diffuse = Plaques that are more than minimal extent; or presence of 
ulcers
•
3 Worse = Plaques were clearly worse than on previous visit
7.3
Mycological Evaluations
All patients will undergo mycological evaluations at baseline and specified
follow-up visits. Samples will be collected by swabbing the affected site. Portions 
of tissue leftover from clinically indicated biopsies may also be requested for 
mycological analysis. Results of mycological evaluations will be presented
semi-quantitatively as:
•
No growth
•
One colony
•
Scant
•
Light
•
Moderate
•
Heavy
•
Indeterminant: Extenuating circumstances preclude classification. 
Measures of mycological response will include:
•
Eradication: No growth.
•
Partial response: Decrease in quantity of Candida from pre-treatment 
levels (eg, from heavy to scant).
•
Persistence: No change or a worsening in Candida burden from 
pre-treatment levels.
•
Relapse: A patient has achieved eradication or partial response initially, 
only to have the infection develop again after initial response or 
eradication.
7.4
Laboratory Evaluations
Stool, Saliva, and Vaginal Secretions
Stool, saliva, and vaginal secretions will be collected for PK analysis and may be 
used for other immunologic or microbiologic studies. Collection of stool and 
vaginal secretions is optional. Stool samples will be continuously collected (as 
available) for 24-hour PK analysis at the NIH Clinical Center on specified days.
Saliva samples will be collected at pre-dose, 8 (± 3 hours) and 24 hours
(± 1 hour) postdose for 24-hour PK analysis. Vaginal fluid will be collected by the 


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patient using the Instead™ Softcup (Evofem, Inc [San Diego, CA, USA]), a 
menstrual fluid collection device. The patient will insert the Softcup 24 hours 
postdose. After 2 hours, the patient will remove the cup and place it in a urine 
specimen container. There is a risk of dislodging an IUD with the Softcup; 
therefore, vaginal fluid collection will not be done in patients with IUDs. Vaginal 
fluid collection will be deferred during a patient’s menstrual period and will not be 
done in patients who have had a hysterectomy with cervix removal.
In the study drug extension phase vaginal fluid will be collected by the subject 
using the Instead™ Softcup. The subject will insert the Softcup and remove it 
after 60 seconds and place it in a Falcon tube container. Vaginal collection is 
done unrelated to study drug administration time.
Urine
Urinalysis includes appearance, glucose, bilirubin, ketone, specific gravity, pH, 
protein, urobilinogen, nitrite, leukocyte esterase, white blood cell count, red blood 
cell count, hemoglobin.
Urine will also be continuously collected for 24-hour PK analysis on specified 
days.
Serum/Urine Pregnancy Test
A serum or urine pregnancy test will be given to women of childbearing potential 
as noted in the Study Schedule. Pregnancy prevention reminders and 
assessment of compliance will be done at each visit for subjects capable of 
becoming pregnant.
Blood Draws
Research evaluations on blood may include, but are not limited to, the following 
laboratory tests:
•
PK
•
Hematology: complete blood count with differential and platelet count
•
Acute care panel, mineral panel, and hepatic panel
Plasma and PBMCs may be collected for storage. Plasma for 24-hour PK 
analysis (6 mL) will be collected in purple top K2-EDTA tubes at predose and 
1 (± 5 minutes), 2 (± 5 minutes), 4 (± 15 minutes), 8 (± 15 minutes),


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10 (± 15 minutes), 12 (± 15 minutes), and 24 hours (± 1 hour) postdose on 
specified days. Intravenous lines will be placed to facilitate multiple sample 
collections over 24 hours. Samples will be processed to measure plasma 
concentrations via a validated liquid chromatography with tandem mass 
spectrometry assay (LC-MS/MS).
8
Potential Risks and Benefits
8.1
Potential Risks
CAMB: There is limited experience in humans for the study drug. In the only 
clinical study on CAMB, side effects included nausea, abdominal pain, vomiting, 
and diarrhea. There was one instance of a moderate upper respiratory tract 
infection in a participant dosed with 800 mg of CAMB, but this was determined to 
not be related to CAMB. Risks associated with non-enchochleated formulations
of AMB include nephrotoxicity, change in clotting factors, anemia, gastrointestinal 
intolerance, allergic reaction, or other unknown risks to this medication. These 
effects have not been observed in healthy humans dosed with CAMB.5 There is 
also the possibility that this treatment will have no effect on the fungal infection   
for which it is being used so the infection may worsen. It is possible that the 
Candida infecting or colonizing the study participant could become resistant to 
amphotericin due to the exposure to the study drug. This could limit treatment 
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The effects of CAMB on the developing fetus are unknown. Therefore, patients 
must use appropriate and effective forms of contraception to avoid becoming 
pregnant or to avoid impregnating their partner.
Endoscopy and Biopsies: Diagnostic endoscopy when performed by a trained 
endoscopist is generally  safe  and  well  tolerated.  Cardiopulmonary  complications 
may account for over  50%  of  the  reported  complications,  with  the  majority  the 
result of  aspiration,  over-sedation,  hypoventilation,   vasovagal   episodes,   and 
airway obstruction.6-9 Significant complications can occur  as  a  result  of 
instrumentation, such as bleeding, perforation,  and  infection,  with  an  overall 
frequency that approximates 0.1% for upper endoscopy.10,11 The risk of
perforation and/or death is approximately 0.001%, but varies with the condition of 
the patient and performance of special procedures such as biopsy.12 These 
endoscopic complications were determined from elderly hospitalized patients, so 
the exact risk is unknown in the population for the current study.
NIH gastroenterologists have extensive experience with performing multiple 
endoscopic biopsies for research purposes and have found these well tolerated 
without appreciably increasing the risk of otherwise routine endoscopy.13 In this 
work, they performed a retrospective review of 253 research endoscopies, for 
which an average of 38 biopsies was obtained per patient. No major 
complications were identified. Minor complications occurred and included self- 
limited bleeding and or pain in 5% of subjects. There was no statistically 
significant association between the number of biopsies, type of procedure, 
location of research biopsies and the risk of complications.
As a general practice, the risk of the procedure is minimized by monitoring pulse, 
blood pressure, and oxygen saturation throughout the procedure and by  
providing inpatient monitoring after the procedure.
In order to prevent complications and minimize their impact, we will avoid 
over-insufflation during biopsies, and provide post-procedure instructions for 
patients to recognize early warning signs of significant complications (eg, 
abdominal pain, fever, hematemesis, melena, chest pain and increased
dysphagia) while providing mechanisms for early evaluation and treatment at the 
NIH CC (providing patient with contact information for on-call physician, study


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team being available to address concerns, having emergency radiology, surgical 
consultation, and endoscopy available).
Conscious Sedation: Conscious sedation may be used in some patients 
undergoing endoscopy. Sedative drugs will be provided by CCMD and/or 
experienced anesthesiologists of the NIH CC. Side effects  from  sedative 
medications include cardiovascular and respiratory depression manifested by
bradycardia, hypotension, respiratory acidosis, and apnea. Additional adverse 
reactions reported with these drugs are stinging or pain at the injection site, 
hiccoughs, nausea, vomiting, postoperative drowsiness and headache, and 
hypersensitivity reactions. Patients will be closely monitored and appropriate 
countermeasures will be taken as necessary.
General Anesthesia: General anesthesia may be used in some patients 
undergoing endoscopy and will be provided by CCMD and/or experienced 
anesthesiologists of the NIH  CC.  Common  side  effects  include  nausea,  vomiting, 
mild allergic  reactions,  headache,  and  dizziness.  Temporary  confusion,  lung 
infection, stroke, heart attack, or death are exceedingly rare side effects. Patients
that undergo general anesthesia will be closely monitored during and after the 
procedure for adverse reactions.
Venous blood draw: Blood drawing may cause pain, bruising, lightheadedness, 
dizziness, possible  fainting,  local  discomfort,  bleeding,   and,   rarely,   infection   at 
the site where the needle is inserted. The amount of blood collected for research 
purposes under this protocol will not exceed the limits allowed for adult and
pediatric research subjects by the NIH CC (http://cc- 
internal.cc.nih.gov/policies/PDF/M95-9.pdf). Additionally, at the time of 
enrollment, the study staff will ask each subject about their participation in other 
research studies to ensure the amount of blood drawn for research purposes 
does not exceed these guidelines.
Vaginal fluid collection using the Instead Softcup: Patient may experience 
pressure as the Instead Softcup is inserted into the vaginal cavity. The patient 
should not feel any discomfort during the secretion collection. The  test is usually  
not painful. There is a risk of dislodging an IUD with the  Instead  Softcup,  so 
vaginal fluid collection will NOT be done in patients with IUDs. There is also a
risk of Toxic Shock Syndrome when the Instead Softcup is left in the vaginal


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cavity for more than 12 hours. Patients will be instructed to remove the Instead 
Softcup after 1 to 2 hours.
Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy 
(APECED): APECED patients are hypoadrenal and therefore require stress-dose 
steroids for any procedure. The risks of inadequate steroid coverage are
hypotension, circulatory collapse, and death. Patients will be closely monitored 
during steroid therapy, and any adverse reactions will be treated appropriately.
Photographs: Having pictures taken may be embarrassing to some people. 
These photographs may be published in medical journals, without identifying the 
participant. We will attempt to preserve the anonymity of the participant as much 
as possible, while providing the information needed to support the research being 
published. Participants may decline photographs or place any restrictions on their
use. Participants will be given the opportunity to discuss this with the PI or AIs.
8.2
Potential Benefits
The individuals we will enroll on this study will be refractory or intolerant to 
standard non-intravenous treatment for mucocutaneous candidiasis infections. 
Patients may not directly benefit from participating in this study. However there is 
the potential benefit that access to this novel formulation of AMB may be   
effective treatment of the Candida infection and result in clinical improvement.
The information obtained in this study may improve the investigators’ 
understanding of the use of CAMB in treating people with refractory 
mucocutaneous candidiasis.
9
Research Use of Stored Human Samples, 
Specimens, or Data
•
Intended Use: Samples and data collected under this protocol may be used 
to study drug levels in plasma, stool, urine, vaginal or salivary secretions to 
understand the pharmacodynamics of the study drug. All of the patients will 
be enrolled on other studies that allow for genetic studies, including whole
exome sequencing, so genetic studies will not be performed as part of this 
study.


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•
Storage: Access to stored samples will be limited using a  locked  freezer 
located in  a  locked  room  with  restricted  access.  Specifically,  PK  blood  and 
data will be  stored  in  the  locked  sample  analysis/storage  room  (key  required)  
of the Clinical Pharmacokinetics Research Laboratory inside of the Clinical
Center Pharmacy Department, which is restricted by badge access to only 
pharmacy department employee. Stool, urine, vaginal and saliva samples will 
be stored in locked Freezer OP11 node 2 probe 88. Samples and data will be 
stored using codes assigned by the investigators. Data will be kept in 
password-protected computers. Only investigators will have access to the 
samples and data. Blood, stool, urine and saliva samples will be sent to 
Lambda Therapeutic Research, Inc. (Toronto, Ontario M1L 4S4, Canada) for 
analysis. Vaginal samples will remain with the Fungal Pathogenesis Unit at 
NIH. PBMC specimen will be stored at the Neutrophil Monitoring Laboratory, 
Leidos Biomedical Research , Inc.
•
Tracking: Samples will be tracked using a database located on a
password-protected computer, which will be maintained by the investigators 
and their designees. Only investigators and their designees will have access 
to this database.
•
Disposition at the Completion of the Protocol:
o
In the future, other investigators (both at NIH and outside) may wish to 
use these samples and/or data for research purposes. If the planned 
research falls within the category of “human subjects research” on the 
part of the NIH researchers, NIH IRB review and approval will be 
obtained. This includes the NIH researchers sending out coded and 
linked samples or data and getting results that they can link back to their 
subjects. Any clinical information shared about the sample would 
similarly require before IRB approval.
•
Reporting the Loss or Destruction of Samples/Specimens/Data to the IRB:
Any loss or unanticipated destruction of samples (for example, due to 
freezer malfunction) or data (for example, misplacing a printout of data 
with identifiers) that meets the definition of a reportable event will be 
reported to the NIH IRB according to NIH Human Research Protection 
Program (HRPP) Policy 801.


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o
Additionally, subjects may decide at any point not to have their samples 
stored. In this case, the principal investigator (PI) will destroy all known 
remaining samples and report what was done to both the subject and to 
the IRB. This decision will not affect the subject’s participation in this 
protocol or any other protocols at NIH.
10
Remuneration Plan for Subjects
Subjects will be compensated for their time and inconvenience. Study subjects 
who complete all study procedures in a dosing cohort will receive $520 plus $200 
for endoscopy (if indicated per protocol). Subjects who do not complete all study 
procedures will receive compensation based on the extent of their participation   
as follows: $200 for the in-patient initial dosing study point and $80 for the serial 
PK blood draw; $40 for the 24 hour admission PK study point and $80 for the 
serial PK blood draw; $30 for each of 4 outpatient blood draws; $200 for 
endoscopy, if indicated per protocol. There will be no compensation for the 
Extension phase of the study, although payment for travel-related expenses will 
be provided according to the NIAID Travel Policy. Payment will be issued 
following the end-of study visit. Volunteers who require additional dosing cohorts 
will receive compensation for the new cohort, as above.
11
Assessment of Safety
11.1
Toxicity Scale
We will utilize National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (MODIFIED) 
(Appendix A).
11.2
Recording/Documentation
At each contact with the subject, information regarding AEs will be elicited by 
appropriate questioning and examinations. All events, both expected/unexpected 
and related/unrelated will be recorded on a source document. Source documents 
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summaries, survey tools, and data collection tools. Source documents will be 
reviewed in a timely manner by the research team. All reportable AEs that are 
identified will be recorded in CRIMSON. The start date, the stop date, the 
severity of each reportable event, and the PI’s judgment of the AE’s relationship 
and expectedness to the study agent/intervention will also be recorded in 
CRIMSON.
11.3
Reporting Procedures
11.3.1
Reporting to the NIH IRB
Reportable events will be tracked and submitted to the NIH IRB as per Policy 801 
(Appendix F) and Policy 802 (Appendix G).
11.3.2
Reporting to the NIAID Clinical Director
The PI will report unanticipated problems (UPs), major protocol deviations, and 
deaths to the NIAID clinical director according to institutional timelines.
11.3.3
Specific Adverse Event Reporting Requirements to the Sponsor
11.3.3.1
Serious Adverse Event Reporting
Any SAE that occurs after the consent is signed until 4 weeks after the last dose 
must be reported to Medpace Clinical Safety (“MedpaceSafety”) whether or not it 
is judged related to the investigational product. All serious adverse events that  
the investigator considers related to study drug occurring 4 weeks after the last 
dose must be reported Medpace Safety.
Serious Adverse Event (SAE)
A Serious Adverse Event is an AE that results in one or more of the following 
outcomes:
•
death.
•
a life-threatening (i.e., an immediate threat to life) event
•
an inpatient hospitalization or prolongation of an existing 


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hospitalization (see note below for exceptions)
•
a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions
•
a congenital anomaly/birth defect.
NOTE: The following hospitalizations are not considered SAEs in this clinical 
study:
•
a visit to the emergency room or other hospital department lasting less 
than 24 hours that does not result in admission (unless considered an 
“important medical event” or a life-threatening event)
•
elective surgery planned before signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of 
health status (e.g., routine colonoscopy)
•
medical/surgical admission for purpose other than remedying ill health 
state that was planned before study entry. Appropriate documentation is 
required in these cases.
•
admission encountered for another life circumstance that carries no 
bearing on health status and requires no medical/surgical intervention 
(e.g., lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative).
To report the SAE, fax or e-mail the completed SAE form to Medpace (fax 
number listed below) within 24 hours of awareness.
Medpace SAE reporting:
e-mail: medpace-safetynotification@medpace.com
Medpace Clinical Safety, US
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3
Facsimile: +1-866-336-5320 or +1-513-570-5196
The Investigator will provide, at a minimum, the protocol number, subject’s 
initials, subject number, date of the SAE, SAE term, and relationship to 


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investigational product. Information identifying the subject must be obliterated 
before transmitting to Medpace Safety.
The PI will notify the IRB of the SAE according to its requirements. An initial 
report followed promptly by a complete report will be forwarded to the IRB, or in 
accordance with the IRB policy.
11.3.3.2
Serious Adverse Event Follow-up
The subject will be observed and monitored carefully until
•
the event resolves, or
•
the event/condition has stabilized (e.g., in the case of persistent 
impairment), or
•
the event returns to baseline, if a baseline value is available.
Within 24 hours of receipt of new information, the updated follow-up SAE form, 
along with any supporting documentation (e.g., subject discharge summary or 
autopsy reports), should be faxed to Medpace Clinical Safety. All efforts must be 
taken to obtain follow-up information promptly.
Follow-up information may consist of:
•
A hospital discharge summary for subjects who are hospitalized or 
hospitalized over a prolonged period due to the SAE. If possible, the 
discharge summary should be obtained when it becomes available.
•
A copy of the autopsy report, if a death occurs and an autopsy is 
performed, should be obtained if possible when  it becomes available.
Any SAEs that are ongoing at the end of treatment or early termination should be 
followed as described above. These data should be recorded on the source 
documents and submitted to the designee on a SAE report form. For ongoing 
SAEs, the investigator must submit follow-up SAE reports to the safety designee 
regarding the subject’s subsequent course until the case is closed.
11.4
Pregnancy
Patients who become pregnant while on study will be taken off the study drug. In 
addition, pregnancies occurring up to 4 weeks after last dose should be reported 
to Medpace Safety. We will assist, as may be appropriate, in referral for 


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pregnancy-related medical attention, including high-risk obstetrical referral if 
requested, and will ask that the patient follow up with us and consent to share 
information as may be appropriate regarding the course and outcome of the 
pregnancy. We will ask for the patient to return for the regularly scheduled clinic 
visits so we can monitor them for any toxicity during the pregnancy. We will 
follow up with the patient after delivery in order to report any further AEs.
The investigator should report the pregnancy to Medpace Clinical Safety within 
24 hours of being notified. Medpace Clinical Safety will then forward the 
Exposure In Utero form to the investigator for completion. If the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE (i.e., 
postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the investigator should follow the procedures for reporting 
an SAE.
11.5
Type and Duration of the Follow-up of Subjects after 
Adverse Events
Investigators will follow AEs until the event has resolved, the condition has 
stabilized, is well characterized, or referred to appropriate medical management, 
whichever comes first. Events and follow-up information occurring after the last 
visit should be recorded in the source documentation. Investigators are not 
obliged to solicit AEs after a subjects’ final visit; however, if an investigator 
learns of an SAE that occurs within 4 weeks after the last dose, then an SAE 
report  form should be submitted to Medpace Safety.
11.6
Pausing Rules for an Individual Subject
Pausing is the suspension of administration of study agent to a single subject 
until a decision is made whether or not to resume administration of the study 
agent.


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The pausing criteria for a single subject in this study include any of the following:
•
A subject experiences a Grade 3 laboratory event that is thought by the 
investigator to be possibly, probably or definitely related to study drug (see 
Appendix A)
•
Any safety issue that the investigator determines should pause 
administration of a study agent to a single subject.
The PI will determine whether or not it is safe to resume administration of the 
study agent to the subject. A subject who does not resume CAMB will continue to 
be followed for safety.
11.7
Stopping Rules for an Individual Subject
A study subject will be discontinued from further study agent administration in the 
event of 1 or more of the following:
•
Gastrointestinal toxicity (nausea/vomiting/diarrhea) that is interfering with 
the ability to perform regular every day activities.
•
A subject experiences two Grade 3 events and/or one Grade 4 event that 
is possibly, probably, or definitely related to participation in the trial;
•
SAE that is possibly, probably or definitely related to the study drug.
•
Any laboratory abnormality, intercurrent illness, other medical condition or 
situation that occurs such that continued participation in the study would 
not be in the best interest of the subject.
•
Any other events that the patient or investigators deems of clinical 
significance.
11.8
Halting Rules for the Protocol
The study will be halted (no new enrollments and no further administration of 
study drug) by the investigators and a report will be submitted to the IRB if 3 or 
more subjects experience one of the following in the 200 mg/day dosage level:
•
serum potassium values of 3 mmol/L or less
•
serum creatine value that is above 1.2 mg/dL and is 50% or more above 
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The IRB, the NIAID, the sponsor, the Food and Drug Administration (FDA), or 
other government agencies, as part of their duties to ensure that research 
subjects are protected, may discontinue the study at any time. Subsequent 
review of serious, unexpected and related AEs by the Medical Monitor, SMC, 
IRB, the sponsor, the FDA, and other regulatory authorities may also result in 
suspension of further trial interventions/administration of study agent at a site. 
The FDA, other regulatory authorities, and the study sponsor retain the authority 
to suspend additional enrollment and study agent administration for the entire 
study as applicable.
11.9
Withdrawal Criteria for an Individual Subject
An individual patient will be withdrawn from the study for any of the following:
•
An individual patient’s decision. (The investigator should attempt to 
determine the reason for the patient’s decision.)
•
Non-compliance with study procedures to the extent that it is potentially 
harmful to the patient or to the integrity of the study data.
•
A patient permanently loses capacity to provide informed consent.
•
The investigator determines that continued participation in the study would 
not be in the best interest of the patient.
Patients who have withdrawn from the study before Day 14 will be replaced. If a 
patient is replaced, then all of their data will still be included for the safety 
assessment.
11.10
Safety Oversight
11.10.1
Safety Monitoring Committee
An independent safety monitoring committee (SMC) consisting of 3 individuals 
will review the study prior to initiation and then after 3 subjects have been on 
study drug for approximately 3 weeks. The SMC will then specify the next 
meeting point. The SMC will focus on subject safety and will include subject 
matter experts. The independent experts do not have direct involvement in the 
conduct of the study and have no significant conflicts of interest as defined by 
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Prior to each SMC review, the PI will submit data as requested by the SMC. After 
each SMC review, a recommendation as to whether the study is to continue, be 
modified, or be terminated will be provided in a summary report. All SAEs, all  
UPs, and all IND Safety Reports will be reported by the PI to the SMC at the  
same time they are submitted to the IRB or IND sponsor. The SMC will be   
notified immediately if pausing, stopping, or halting rules are met, and the SMC 
will provide a recommendation for continuation, modification, or termination of the 
study. The PI will submit the written SMC summary reports with   
recommendations to the IRB.
12
Clinical Monitoring Structure
12.1
Site Monitoring Plan
An initiation meeting will be conducted by Matinas Biopharma Nanotechnologies, 
Inc. or an approved representative. At this meeting, the protocol and data 
collection procedures will be reviewed with the PI and all study staff.
Monitoring visits will be conducted during the study by Matinas Biopharma 
Nanotechnologies, Inc. or designee. The PI will make a reasonable amount of 
time available to the CRA on reasonable notice to assist with monitoring.
At each visit, the CRA will review CRIMSON data abstracts and source 
documents to ensure that all items have been completed and that the data 
provided are accurate and obtained in the manner specified in the protocol.
As per ICH-GCP 5.18 and FDA 21 CFR 312.50 clinical protocols are required 
to be adequately monitored. At the request of the NIAID Clinical Director this 
protocol monitoring for the NIH site will be conducted according to the “NIAID 
Intramural Clinical Monitoring Guidelines.” Monitors under contract to the 
NIAID/OCRPRO will visit the NIH site to monitor aspects of the study in 
accordance with the appropriate regulations and the approved protocol. The 
objectives of a monitoring visit will be: 1) to verify the existence of signed  
informed consent documents and documentation of the ICF process for each 
monitored subject; 2) to verify the prompt and accurate recording of all 
monitored data points, and prompt reporting of all SAEs; 3) to compare 
abstracted information from CRIMSON data abstracts with individual subjects’ 


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records and source documents (subjects’ charts, laboratory analyses and test 
results, physicians’ progress notes, nurses’ notes, and any other relevant 
original subject information); and 4) to help ensure investigators are in 
compliance with the protocol. The monitors also will inspect the clinical site 
regulatory files to ensure that regulatory requirements (Office for Human 
Research Protections-OHRP), FDA, and applicable guidelines (ICH-GCP) are 
being followed. During the monitoring visits, the investigator (and/or designee) 
and other study personnel will be available to discuss the study progress and 
monitoring visit.
The investigator (and/or designee) will make study documents (e.g., consent 
forms, CRIMSON data abstracts and pertinent hospital or clinical records readily 
available for inspection by the local IRB, FDA, the site monitors, and the NIAID 
staff for confirmation of the study data.
A specific protocol monitoring plan will be discussed with the Principal 
Investigator and study staff. The plan will outline the frequency of monitoring 
visits based on such factors as study enrollment, data collection status and 
regulatory obligations.
12.2
Auditing Procedures
In addition to the monitoring visits outlined above, an investigational site may 
undergo a quality assurance audit. Matinas Biopharma Nanotechnologies, Inc., 
its authorized representative, or a regulatory agency such as the FDA may 
conduct the audit. If a regulatory agency requests an audit of the study site, the 
Investigator is required to inform Matinas Biopharma Nanotechnologies, Inc. 
immediately.
13
Statistical Considerations
13.1
Study Hypotheses
CAMB will improve clinical symptoms of mucocutaneous candidiasis 
(OC/EC/VVC) in patients that are refractory or intolerant to standard non- 


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intravenous therapies.
13.2
Sample Size Justification
Sixteen patients will be accrued to the study. This sample size will provide 
80% power to distinguish between true underlying improvement in clinical
symptom rates of 5% and 25% using a 0.043 significance level. The 0.043 type I 
error rate will be used since the small sample size and yes/no endpoint do not 
allow for a 0.05 level test. The 0.043 level is as close to 0.05 as possible without 
being larger than 0.05.
The 5% rate with standard of care is based on historical observations at the 
clinical center that in this immune deficient population few if any patients have 
sustained improvement.
With 16 patients there will be a probability of 0.8 (80% power) of observing 3 or 
more responses if the true response rate with CAMB treatment is 25%. There will 
be a 0.043 (type I error rate) probability of observing 3 or more responses if the 
true response rate with CAMB is 5% (no better than current treatments).
Analysis Populations
The safety population will comprise all subjects who received at least one dose of 
investigational product.
13.3
Description of the Analyses
13.3.1
Efficacy Statistical Analysis
If 3 or more clinical improvements in symptoms are observed out of the 16 
patients we will conclude there is promising evidence to continue studying 
CAMB. With this criteria there is a 0.043 probability of concluding CAMB is 
promising when the true rate of clinical improvement is 5% (no better than 
current treatments) and there is an 0.8 probability of concluding CAMB is 
promising when the true rate is 25% (improvement over current treatments).
If extra patients (up to the maximum of 20 patients) are accrued to the study the 
data will be analyzed to maintain type I error rate less than 0.05.


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13.3.2
Safety Analysis
Safety analyses will include where appropriate, descriptive statistics, counts, and 
percentages.
Adverse Events
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by System Organ Class (SOC) and Preferred Term for each 
treatment group. All AEs will be captured after the first dose through the final visit 
or ET visit.
AEs will be summarized by presenting:
• The number and percentage of subjects experiencing any AE
• The number and percentage of subjects experiencing any AE by SOC
• The number and percentage of subjects experiencing any SAE
• The number and percentage of subjects experiencing any AE associated 
with study discontinuation
Clinical Laboratory Parameters
Clinical laboratory measurements (serum creatinine, potassium, CRP, ALT, AST) 
and changes from baseline to end-of-treatment will be summarized descriptively 
for each visit with the mean, median, standard deviation (SD), minimum, and 
maximum, by treatment group.
Vital Signs
Vital signs will be summarized descriptively for the mean, median, SD, minimum, 
and maximum by treatment group.
13.3.3
PK Analysis
Plasma drug levels will be determined predose and at 1 (± 5 minutes), 2 
(± 5 minutes), 4 (± 15 minutes), 8 (± 15 minutes), 10 (± 15 minutes), 12
(± 15 minutes), and 24 hours (± 1 hour) postdose on Days 1 and 14 (all
dosages), 21 (200 mg/day), 27 (400 and 800 mg/day), and 40 (800 mg/day). Blood samples will 
be processed to measure plasma concentrations via a validated LC-MS/MS assay. Twenty-
four-hour urine collections will have total volume recorded and a 10-mL sample aliquoted to 
measure concentrations via a validated LC-MS/MS assay. Saliva collected at predose and at 8 


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(±3 hours) and 24 (±1 hours) hours postdose on Days 1 and 14 (± 3 days) of each dosage level 
will be analyzed to measure concentrations via LC-MS/MS assay. Stool samples will be 
collected during the 24 hours after the initial dose, and at Day 14
(± 3 days) days of each dosage. Vaginal secretions will be collected between
24-26 hours postdose on Days 1 and 14 (± 3 days) of each dosage level and will 
be analyzed to measure concentrations via LC-MS/MS assay. The stool and 
vaginal samples will be optional for subjects.
Blood, stool, urine and saliva samples will be analyzed by Lambda Therapeutic 
Research Inc. (460 Comstock Road, Toronto, Ontario, M1L 4S4, Canada) CAMB 
plasma PK parameters will be determined using noncompartmental methods with 
Phoenix® WinNonlin® software (version 6.03; Pharsight Corporation, Mountain 
View, CA). Maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) 
will be obtained directly by observation of the plasma concentration vs. time 
profiles. The apparent elimination rate constant (λZ) will be determined by 
calculating the absolute value of the slope of the log–linear regression of at least  
2 points of the plasma concentration–time plot (when reported). The elimination 
half-life (T1/2) will be calculated as 0.693/λZ (when reported). The steady-state 
area under the concentration vs. time curve (AUC) from time 0 to 24 hours 
postdose (AUC0-24) will be calculated using the linear (up)/logarithmic (down) 
trapezoidal rule with a minimum of four quantifiable concentrations. Dose 
proportionality (linearity) will be assessed by comparison of geometric means of 
AUC and Cmax PK parameters among dose levels. The percentage of total 
administered dose excreted in urine will be determined and used to calculate the 
renal elimination rate constant and renal clearance. Saliva levels will be reported 
as descriptive data.
14
Ethics/Protection of Human Subjects
14.1
Informed Consent Process
Informed consent is a process where information is presented to enable persons 
to voluntarily decide whether or not to participate as a research subject. It is an 
ongoing conversation between the human research subject and the researchers, 
which begins before consent is given and continues until the end of the subject's 
involvement in the research. Discussions about the research will provide  
essential information about the study and include purpose, duration,  


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experimental procedures, alternatives, risks, and benefits. Subjects will be given 
the opportunity to ask questions and have them answered.
The subjects will sign the informed consent document before undergoing any 
research procedures. The subjects may withdraw consent at any time throughout 
the course of the trial. A copy of the informed consent document will be given to 
the subjects for their records. The researcher will document the signing of the 
consent form in the subject’s medical record. The rights and welfare of the 
subjects will be protected by emphasizing to them that the quality of their medical 
care will not be adversely affected if they decline to participate in this study.
14.1.1
Remote Consent Process
During the coronavirus disease 2019 pandemic, reconsent will be obtained 
remotely from the final enrolled participant.
The informed consent document will be sent via secure email or file transfer to 
the potential participant. An explanation of the study will be provided over the 
telephone or NIH-approved video conferencing platform (e.g., Zoom, Microsoft 
Teams) after the participant has had the opportunity to read the consent form. 
The participant can print the appropriate form to sign and date in ink, or they can 
sign and date digitally using a stylus or mouse.
The participant will return the signed and dated consent form to the consenting 
investigator, who will sign and date it with the date it was received. The consent 
form can either be printed and signed and dated in ink, or signed and dated 
digitally. A fully executed copy will be sent to the participant for their records.
The informed consent process will be documented on a progress note by the 
consenting investigator. The investigator will confirm that written consent has 
been obtained prior to initiating any study interventions.
14.2
Subject Confidentiality
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor. This confidentiality is extended to cover 
testing of biological samples in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all records 
will be kept confidential to the extent provided by federal, state and local law. No 
information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 


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All research activities will be conducted in as private a setting as possible.
The study monitors and other authorized representatives of the Sponsor, 
representatives of the IRB, and/or regulatory agencies may inspect all documents 
and records required to be maintained by the Investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical 
site for internal use during the study. At the end of the study, all records will 
continue to be kept in a secure location for as long a period as dictated by the 
reviewing IRB, institutional policies, or Sponsor requirements. 
Records will be kept locked and all computer entry and networking programs will 
be done with coded numbers only. Only investigators will have access to the code 
key. Clinical information will not be released without written permission of the 
subject, except as necessary for monitoring by the IRB, the FDA, NIAID, OHRP, or 
the sponsor’s designee.
For subjects residing outside the local (Bethesda, MD) area, blood samples for 
safety labs ( CBC with diff, Comprehensive BMP), may be drawn and processed 
at Quest Diagnostics, LabCorp, or by a primary care doctor. These samples may 
be labeled with a StudyID (i.e. Matinas MB70004), gender, and date of birth, as 
required by the local facility.
To further protect the privacy of study participants, a Certificate of Confidentiality 
has been issued by the NIH. This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have 
access to research records to refuse to disclose identifying information on 
research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers 
and institutions from being compelled to disclose information that would identify 
research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality 
and privacy to participants.


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15
Data Handling and Record Keeping
15.1
Data Capture and Management
Study data will be maintained in CRIMSON, and collected directly from subjects 
during study visits and telephone calls, or will be abstracted from subjects’  
medical records. Source documents include all recordings of observations or 
notations of clinical activities and all reports and records necessary to confirm the 
data abstracted for this study. Data entry into CRIMSON will be performed by 
authorized individuals. The Investigator is responsible for assuring that the data 
collected are complete, accurate, and recorded in a timely manner.
15.2
Record Retention
The investigator is responsible for retaining all essential documents listed in the 
ICH GCP Guideline. Study records will be maintained by the PI in accordance 
with CFR 312.62 and in compliance with institutional, IRB, state, and federal 
medical records retention requirements, whichever is longest. All stored records 
will be kept confidential to the extent required by federal, state, and local law.


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16
Scientific References
1.
Santangelo R, Paderu P, Delmas G, et al. Efficacy of oral cochleate- 
amphotericin B in a mouse model of systemic candidiasis. Antimicrobial 
agents and chemotherapy. 2000;44(9):2356-2360.
2.
Delmas G, Park S, Chen ZW, et al. Efficacy of orally delivered cochleates 
containing amphotericin B in a murine model of aspergillosis. Antimicrobial 
agents and chemotherapy. 2002;46(8):2704-2707.
3.
Kalbag S, Lu R, Ngoje J, Mannino RJ. Oral Administration of Bioral™ 
Amphotericin B: Toxicokinetic Studies in Animal Models. Focus on Fungal 
Infections 19; March 4-6, 2009; Sanibel Island, FL, USA.
4.
Biederdorf FA, Breithaupt I, Mannino RJ, Blum DE. Administration of 
Bioral™ Amphotericin B (BAmB) in Humans: a Phase I Study of 
Tolerability and Pharmacokinetics. Focus on Fungal Infections 19; March 
4-6, 2009; Sanibel Island, FL, USA.
5.
Amphotericin B Chochleates (CAmB) Investigator's Brochure edition 4. 
Aquarius Biotechnologies, Inc., Chicago, IL; October 2014.
6.
Keeffe EB. Sedation and analgesia for endoscopy. Gastroenterology.
1995;108(3):932-934.
7.
Lieberman DA, Wuerker CK, Katon RM. Cardiopulmonary risk of 
esophagogastroduodenoscopy. Role of endoscope diameter and systemic 
sedation. Gastroenterology. 1985;88(2):468-472.
8.
Sharma VK, Nguyen CC, Crowell MD, Lieberman DA, de Garmo P, 
Fleischer DE. A national study of cardiopulmonary unplanned events after 
GI endoscopy. Gastrointestinal endoscopy. 2007;66(1):27-34.
9.
Silvis SE, Nebel O, Rogers G, Sugawa C, Mandelstam P. Endoscopic 
complications. Results of the 1974 American Society for Gastrointestinal 
Endoscopy Survey. Jama. 1976;235(9):928-930.
10.
Carey WD, Boayke A, Leatherman J. Spontaneous bacterial peritonitis: 
clinical and laboratory features with reference to hospital-acquired cases. 
The American journal of gastroenterology. 1986;81(12):1156-1161.
11.
Sieg A, Hachmoeller-Eisenbach U, Eisenbach T. Prospective evaluation of 
complications in outpatient GI endoscopy: a survey among German 
gastroenterologists. Gastrointestinal endoscopy. 2001;53(6):620-627.
12.
McLernon DJ, Donnan PT, Crozier A, Dillon J, Mowat C. A study of the 
safety of current gastrointestinal endoscopy (EGD). Endoscopy. 
2007;39(8):692-700.
13.
Yao MD, von Rosenvinge EC, Groden C, Mannon PJ. Multiple endoscopic 
biopsies in research subjects: safety results from a National Institutes of 
Health series. Gastrointestinal endoscopy. 2009;69(4):906-910.


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Appendix A Toxicity Table
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, DIVISION OF 
MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT TOXICITY 
TABLE (MODIFIED)
ABBREVIATIONS: Abbreviations utilized in the Table:
ULN = Upper Limit of Normal
LLN = Lower Limit of 
Normal
Rx = Therapy
Req = Required
Mod = Moderate
IV = Intravenous 
ADL = Activities of Daily Living
Dec = Decreased
ESTIMATING SEVERITY GRADE
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale 
below to estimate grade of severity:
GRADE 1
Mild: Transient or mild discomfort (<48 hours); no 
medical intervention/therapy required
GRADE 2
Moderate: Mild to moderate limitation in activity - 
some assistance may be needed; no or minimal 
medical intervention/therapy required
GRADE 3
Severe: Marked limitation in activity, some 
assistance usually required; medical 
intervention/therapy required, hospitalizations 
possible.
GRADE 4
Life-threatening: Extreme limitation in activity, 
significant assistance required; significant medical 
intervention/therapy required, hospitalization  or 
hospice care probable


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SERIOUS OR LIFE-THREATENING AEs
ANY clinical event deemed by the clinician to be serious or life-threatening 
should be considered a grade 4 event.
LABORATORY RANGES
Where discrepancies in the ULN and LLN of laboratory ranges occur between 
those included in this document and those of the laboratory that performs the 
assays, the values provided by the laboratory will be used for assignment of 
severity grade.
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
9.5 - 10.5 gm/dL
8.0 - 9.4 gm/dL
6.5 - 7.9 gm/dL
< 6.5 gm/dL
Absolute Neutrophil 
Count
1000-1500/mm3
750-999/mm3
500-749/mm3
<500/mm3
Platelets
75,000-
99,999/mm3
50,000-
74,999/mm3
20,000-
49,999/mm3
<20,000/mm3
WBCs
11,000-13,000/
mm3
13,000-15,000
/mm3
15,000-
30,000/mm3
>30,000 or
<1,000 mm3
% Polymorphonuclear 
Leucocytes + Band 
Cells
> 80%
90 – 95%
>95%
---------
Activated Partial 
Thromboplastin (APTT)
1.01 -1.66 × ULN
1.67 - 2.33 ×
ULN
2.34 - 3 × ULN
> 3 × ULN
CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4


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Hyponatremia
130-135 mEq/L
123-129 mEq/L 116-122 mEq/L
< 116 mEq/L or 
abnormal sodium 
with mental status 
changes or 
seizures
Hypernatremia
146-150 mEq/L
151-157 mEq/L 158-165 mEq/L
> 165 mEq/L or 
abnormal sodium 
with mental status 
changes or 
seizures
Hypokalemia
3.0 - 3.4 mEq/L
2.5 - 2.9 mEq/L 2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required
< 2.0 mEq/L or 
abnormal 
potassium with 
paresis, ileus or 
life-threatening 
arrhythmia
Hyperkalemia
5.6 - 6.0 mEq/L
6.1 - 6.5 mEq/L 6.6 - 7.0 mEq/l
> 7.0 mEq/L or 
abnormal 
potassium with 
life-threatening 
arrhythmia
Hypoglycemia
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
<30 mg/dL or 
abnormal glucose 
with mental status 
changes or coma
Hyperglycemia 
(nonfasting and no prior 
diabetes)
116 - 160 mg/dL
161- 250 mg/dL 251 - 500 mg/dL
> 500 mg/dL or 
abnormal glucose 
with ketoacidosis 
or seizures
Hypocalcemia(corrected 
for albumin)
8.4 - 7.8 mg/dL
7.7 - 7.0 mg/dL
6.9 - 6.1 mg/dL
< 6.1 mg/Dl or 
abnormal calcium 
with life 
threatening 
arrhythmia or 
tetany


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Hypercalcemia (correct 
for albumin)
10.6 - 11.5 mg/dL
11.6 -
12.5 mg/dL
12.6 - 13.5 mg/dL
> 13.5 mg/dL or 
abnormal calcium 
with life 
threatening 
arrhythmia
Hypomagnesemia
1.4 - 1.2 mEq/L
1.1 - 0.9 mEq/L 0.8 - 0.6 mEq/L
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia
Hypophosphatemia
2.0 - 2.4 mg/dL
1.5 -1.9 mg/dL 
or replacement 
Rx required
1.0 -1.4 mg/dL 
intensive therapy 
or hospitalization 
required
< 1.0 mg/dL or 
abnormal 
phosphate with 
life-threatening 
arrhythmia
Hyperbilirubinemia 
(when accompanied by 
any increase in other 
liver function test)
1.1 - <1.25 x ULN
1.25 - <1.5 x 
ULN
1.5 – 1.75 x ULN
> 1.75 x ULN
Hyperbilirubinemia 
(when other liver 
function are in the 
normal range)
1.1 - <1.5 x ULN
1.5 - <2.0 x 
ULN
2.0 – 3.0 x ULN
> 3.0 x ULN
BUN
1.25 - 2.5 x ULN
2.6 - 5 x ULN
5.1 - 10 x ULN
> 10 x ULN
Hyperuricemia (uric 
acid)
7.5 – 10.0 mg/dL
10.1 –
12.0 mg/dL
12.1 – 15.0 mg/dL
>15.0 mg/dL
Creatinine
1.1 - 1.5 x ULN
1.6 - 3.0 x ULN
3.1 - 6 x ULN
> 6 x ULN or 
dialysis required
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT)
1.1 - <2.0 x ULN
2.0 – <3.0 x 
ULN
3.0 – 8.0 x ULN
> 8 x ULN


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ALT (SGPT)
1.1 - <2.0 x ULN
2.0 – <3.0 x 
ULN
3.0 – 8.0 x ULN
> 8 x ULN
Alkaline Phosphatase
1.1 - <2.0 x ULN
2.0 – <3.0 x 
ULN
3.0 – 8.0 x ULN
> 8 x ULN
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+ or 200 mg - 1 
gm loss/day
2-3+ or 1- 2 gm 
loss/day
4+ or 2-3.5 gm 
loss/day
nephrotic 
syndrome
or
> 3.5 gm loss/day
Hematuria
microscopic only
<10 rbc/hpf
gross, no clots
>10 rbc/hpf
gross, with or 
without clots, OR 
red blood cell casts
obstructive or 
required 
transfusion
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Rhythm
asymptomatic, 
transient signs, 
no Rx required
recurrent/persistent 
symptomatic Rx 
required
unstable 
dysrhythmia; 
hospitalization 
and treatment 
required
Hypertension
transient increase
> 20 mm/Hg; no 
treatment
recurrent, 
chronic 
increase
> 20mm/Hg.
/treatment 
required
acute treatment 
required; 
outpatient 
treatment or 
hospitalization 
possible
end organ 
damage or 
hospitalization 
required


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Hypotension
transient  
orthostatic 
hypotension with 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic BP, 
No treatment 
required
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable with 
oral fluid 
treatment
requires IV fluids; 
no hospitalization 
required
mean arterial 
pressure
<60mm/ Hg or 
end organ 
damage or shock; 
requires 
hospitalization 
and vasopressor 
treatment
Pericarditis
minimal effusion
mild/moderate 
asymptomatic 
effusion, no 
treatment
symptomatic 
effusion; pain; 
EKG changes
tamponade; 
pericardiocentesis 
or surgery 
required
Hemorrhage, Blood 
Loss
microscopic/occult
mild, no 
transfusion
gross blood loss;
1-2 units 
transfused
massive blood 
loss; > 3 units 
transfused
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
transient- no 
treatment
persistent 
cough;
treatment 
responsive
Paroxysmal cough; 
uncontrolled with 
treatment
--------------------
Bronchospasm, Acute
transient; no 
treatment;
70% - 80% FEV1
of peak flow
requires 
treatment; 
normalizes with 
bronchodilator;
FEV1 50% -
70%
(of peak flow)
no normalization 
with 
bronchodilator;
FEV1 25% - 50%
of peak flow; or 
retractions present
cyanosis: FEV1
< 25%
of peak flow or 
intubation 
necessary
Dyspnea
dyspnea on 
exertion
dyspnea with 
normal activity
dyspnea at rest
Dyspnea 
requiring oxygen 
therapy


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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
mild or transient; 
maintains 
reasonable intake
moderate 
discomfort; 
intake 
decreased 
significantly; 
some activity 
limited
no significant 
intake; requires IV 
fluids
hospitalization 
required;
Vomiting
1 episode in 24 
hours
2-5 episodes in
24 hours
>6 episodes in 24 
hours or needing 
IV fluids
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral 
nutrition
Constipation
requiring stool 
softener or dietary 
modification
requiring 
laxatives
obstipation 
requiring manual 
evacuation or 
enema
obstruction or 
toxic megacolon
Diarrhea
mild or transient; 3- 
4 loose stools/day 
or mild diarrhea 
last < 1 week
moderate or 
persistent; 5-7 
loose 
stools/day or 
diarrhea lasting
>1 week
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required
hypotensive 
shock or 
physiologic 
consequences 
requiring 
hospitalization
Oral 
Discomfort/Dysphagia
mild discomfort; no 
difficulty 
swallowing
some limits on 
eating/drinking
eating/talking very 
limited; unable to 
swallow solid foods
unable to drink 
fluids; requires IV 
fluids


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Neuro-Cerebellar
slight 
incoordination 
dysdiadochokinesis
intention 
tremor, 
dysmetria, 
slurred speech; 
nystagmus
locomotor ataxia
Incapacitated
Psychiatric
mild anxiety or 
depression
moderate 
anxiety or 
depression; 
therapy 
required; 
change in 
normal routine
severe mood 
changes requiring 
therapy; or suicidal 
ideation; or 
aggressive 
ideation
acute psychosis 
requiring 
hospitalization; 
or suicidal 
gesture/attempt 
or hallucinations
Muscle Strength
subjective 
weakness, no 
objective 
symptoms/ signs
mild objective 
signs/symptoms 
no decrease in 
function
objective 
weakness function 
limited
Paralysis
Paresthesia (burning, 
tingling, etc.)
mild discomfort; no 
treatment required
moderate 
discomfort; non- 
narcotic 
analgesia 
required
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement
incapacitating; or 
not responsive to 
narcotic 
analgesia
Neuro-sensory
mild impairment in 
sensation 
(decreased 
sensation, e.g. 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing
moderate 
impairment 
(mod 
decreased 
sensation, e.g. 
vibratory, 
pinprick, 
hot/cold to 
ankles) and/or 
joint position or 
mild impairment 
that is not 
symmetrical
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod 
degree in multiple 
different body 
areas (i.e. upper 
and lower 
extremities)
sensory loss 
involves limbs 
and trunk; 
paralysis; or 
seizures


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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia (joint pain)
mild pain not
moderate pain,
severe pain; pain
disabling pain
interfering with
analgesics
and/or analgesics
function
and/or pain
interfering with
interfering with
activities of daily
function but not living
with activities of
daily living
Arthritis
mild pain with
moderate pain
severe pain with
permanent and/or
inflammation,
with
inflammation,
disabling joint
erythema or joint
inflammation,
erythema or joint
destruction
swelling – but not
erythema or
swelling –and
interfering with
joint swelling –
interfering with
function
interfering with
activities of daily
function, but not living
with activities of
daily living
Myalgia
Myalgia with no
muscle
severe muscle
frank
limitation of activity tenderness (at
tenderness with
myonecrosis
other than
marked impairment
injection site) or of activity
with moderate
impairment of
activity


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SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Mucocutaneous
erythema; pruritus
diffuse, maculo 
papular rash, 
dry 
desquamation
vesiculation or 
moist 
desquamation or 
ulceration
exfoliative 
dermatitis, 
mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected 
Stevens-Johnson 
or necrosis 
requiring surgery
Induration
< 15mm
15-30 mm
>30mm
Erythema
< 15mm
15-30 mm
>30mm
Edema
< 15mm
15-30 mm
>30mm
Rash at Injection Site
< 15mm
15-30 mm
>30mm
Pruritus
slight itching at 
injection site
moderate 
itching at 
injection 
extremity
itching over entire 
body
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Allergic Reaction
pruritus without 
rash
localized 
urticaria
generalized 
urticaria; 
angioedema
Anaphylaxis
Headache
mild, no treatment 
required
transient, 
moderate; 
treatment 
required
severe; responds 
to initial narcotic 
therapy
intractable; 
requires repeated 
narcotic therapy


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Fever: oral
37.7 - 38.5° C or
100.0 - 101.5 °F
38.6 - 39.5 °C
or 101.6 - 102.9
°F
39.6 - 40.5 °C or
103 - 105 °F
> 40 °C or > 105
°F
Fatigue
normal activity 
reduced < 48 hours
normal activity 
decreased 25-
50% > 48 hours
normal activity 
decreased > 50% 
can’t work
unable to care for 
self


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Appendix B Schedule of Procedures/Evaluations
Study Schedule (Days)
1c
2
4
7 b
(± 1)
14 
(±
3)c,d,m
If escalating, move to next row. No visits until Day 21 if 
continuing on 200 mg.d
21 b
(±
3)
28 
(±
3)
42 b
(±
3)
Screeni 
ng
(-14 to -
1)a
0
200-mg Dosage Phase
14 
(± 3)c
15 
(±
3)
17 
(±
2)
20 b
(± 2)
27 
(±
3)c,e,m
If escalating, move to next 
row. No visits until Day 34 if
continuing on 400 mg.e
34 b
(±
3)
41 
(±
3)
55 b
(±
3)
400-mg Dosage Phase
27 
(± 3)c
28 
(±
3)
30 
(±
2)
33 b
(± 2)
40
(± 3)
c,m
47 b
(±
3)
54 
(±
3)
68 b
(±
3)
800-mg Dosage Phase
ET
Informed 
Consent
X
Medical/Medicati 
on History
X
X
Clinical 
Assessment/
Physical Exam
X
X
Xf
X
Xf
X
Xf
X
Xf
X
X
GYN Exam, if 
applicable
X
X
X
X
X
X
Endoscopyg
X
X
Adverse Events 
and
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Acute, Hepatic, 
Mineral Panels
X
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy 
Testingi
X
Xf
Xf
Xf
Xf
X
X
Plasma PKj
X
X
X
X
Xk
Urine PKl
X
X
X
X
Saliva PKm
X
X
X
X
Stool PKl
X
X
X
X
OMC Pictures
X
X
X
X
X
X
X
Vaginal 
Secretion n
X
X
X
X
Xp
Microbiology 
(fungal culture)
X
Xh
X
X
X
X
X
Stored
SamplesoSampl 
esl
X
X
X
X
X
X


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ET = early termination; PK = pharmacokinetics; PT/PTT = prothrombin/partial thromboplastin; X = to be performed.
a
Screening data will be collected from other protocols on which patients are enrolled. If screening data are older than 14 days, then procedures will be conducted 
again under this protocol.
b
For these timepoints the patient and investigator have the option of doing a phone interview and obtaining lab work at a local laboratory. A copy of the results 
should be sent to the investigator.
c
On these days, patients will only receive the morning dose.
d
If the patient is a clinical responder on Day 14 and the study drug is well tolerated, then they will continue with their dosage for another 14 days. If they are not a 
clinical responder but the study drug is well tolerated, then the dosage will increase to 400 mg/day.
e
If the patient is a clinical responder on Day 27 and the study drug is well tolerated, then they will continue with their dosage for another 14 days. If they are not a 
clinical responder but the study drug is well tolerated, then the dosage will increase to 800 mg/day.
f
On these days, clinical assessment, physical exam, and pregnancy testing will be conducted before the morning dose is administered.
g
Patients with a diagnosis of esophageal candidiasis will undergo a clinically indicated endoscopic evaluation within 4 weeks before study drug initiation. These 
patients will also undergo a second, research-indicated endoscopy at end of treatment or within 4 weeks of clinical improvement, whichever occurs first.
h
If these evaluations have been conducted for screening within 72 hours of Day 0, then they do not need to be repeated on Day 0. 
i
Urine or plasma. Patients of childbearing potential only.
j
Blood for 24-hour PK analysis will be collected predose and at 1 (± 5 minutes), 2 (± 5 minutes), 4 (± 15 minutes), 8 (± 15 minutes), 10 (± 15 minutes), 12 
(± 15 minutes), and 24 hours (± 1 hour) postdose. Patients will only receive the morning dose on the days that 24-hour PK samples are collected.
k
At Days 28, 41 and 54 study visits (before the morning dose), samples will only be collected once. Samples will be used for trough PK (final) analysis and not a 24- 
hour PK analysis.
l
Continuous collection of urine and stool samples throughout the designated 24-hour period. Collection of stool is optional. 
m
Saliva will be collected predose and at 8 (± 3 hours) and 24 (± 1 hours) hours postdose.
n
Vaginal secretions will be collected at baseline and between 24-26 hours postdose. Sample collection will be voluntary 
o
Peripheral blood mononuclear cells. Sample collection will be voluntary
p
Vaginal secretions will be collected between 24-26 hours postdose. Sample collection will be voluntary. This collection will be done on Day 41 of the 800mg dosing 
cohort.
q
Option to enter the Extension study if clinical responder status obtained at 2 weeks at the highest tolerated dose at which patient responds.


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Appendix C Blood Volumes for Specimen Collection
Study Schedule (Days)
1
2
4
7
(± 1)
14
(± 3)
If escalating, move to next row. No visits until Day 21 if continuing 
on 200 mg.
21
(± 3)
28
(± 3)
42
(± 3)
Screening 
(-14 to -1)
0
200-mg Dosage Phase
14
(± 3)
15
(± 3)
17
(± 2)
20
(± 2)
27
(± 3)
If escalating, move to next row.
No visits until Day 34 if 
continuing on 400 mg.
34
(± 3)
41
(± 3)
55
(± 3)
400-mg Dosage Phase
27
(± 3)
28
(± 3)
30
(± 2)
33
(± 2)
40
(± 3)
47
(± 3)
54
(± 3)
68
(± 3)
800-mg Dosage Phase
Volume (mL)
Hematology
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Acute, Hepatic, 
Mineral Panels
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Pregnancy Testing
4
4
4
4
4
4
Plasma PK
48
48
48
48
6
Stored Samples
10
10
10
10
10
Daily Volume
11
17
59
7
7
7
69
7
7
11.5
69
7
7
7
69
7
27
7
Cumulative Volume 
200-mg Dosage
11
28
87
94
101
108
177
184
211
218
Cumulative Volume 
400-mg Dosage
11
28
87
94
101
108
177
184
191
198
267
274
301
308
Cumulative Volume 
800-mg Dosage
11
28
87
94
101
108
177
184
191
198
267
274
281
288
357
364
391
398
-==


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Appendix D Schedule of Procedures/Evaluations – Extension Study
Extension 
Entry1
Bi-weekly 
Visits to 
NIH +/- 3
days) for 
first 
month 
after 
extension 
study 
entry2
Bi- 
weekly 
safety 
labs 
(every 
2
weeks
+/- 4
days) 
at NIH 
or 
local 
lab3
Monthly 
phone 
calls +/- 
4 days 
(at 2 
week 
interim 
between 
quarterly 
NIH
visits)
Quarterly 
visits to 
NIH
(every 
12-
weeks
+/- 
7days)4
Informed consent
x
Clinical 
Assessment/Physical 
Exam
x
x
x
x
Adverse Events and 
Concomitant 
Medications, drug 
compliance
x
x
x
x
x
GYN Exam if 
applicable
x
x
x
Hematology 
(CBC/Diff)
x
x
x
x
Chemistry (Acute, 
Hepatic, Mineral 
Panels)
x
x
x
x
Urinalysis
x
x
x
Pregnancy Testing
x
x
Microbiology (fungal 
culture)
x
x
x
Stored Samples 
(serum & PBMC) 5
x
x
x
Urine, plasma, stool, 
saliva and vaginal 
secretions5
x
x
x
OMC pictures
x
x
1. All procedures/evaluations for extension study entry are to be conducted during 
the last treatment visit of the primary study.
2. Bi-weekly visits to NIH will be performed in-person at NIH Clinical Center 
every 2-weeks during first month of the extension.


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3. Bi-weekly lab draws can be done at the NIH Clinical Center or at the home 
laboratory. If the visits are conducted at NIH a clinical assessment/physical 
exam will be performed along with adverse event and concomitant medication 
collection.
4. After the first month of the extension, in person visits to the NIH Clinical 
Center will be quarterly. The 3-month visits will go out to 60 months from the 
Extension Entry visit. If a patient chooses to terminate the Extension study 
prior to the 60-month visit, the same monthly procedures/evaluations will be 
conducted at the Early Termination visit as the Monthly visits.
5. These collections are optional.


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Appendix E Blood Volumes for Specimen Collection – Extension Study
Study Week
Visit
Hematology (3)
Acute, Hepatic, 
Mineral Panel (4)
Pregnancy 
Testing (4)
Stored Samples 
(10)
Plasma (6)
Total Per Visit 
(mL)
Cummulative Total
(mL)
Week 2
Biweekly at NIH
3
4
10
6
23
23
Week 4
Monthly at NIH
3
4
4
10
6
27
50
Week 6
Bi-weekly
3
4
7
57
Week 8
Bi-weekly
3
4
7
64
Week 10
Bi-weekly
3
4
7
71
Week 12
Bi- weekly
3
4
7
78
Week 14
Bi-weekly
3
4
7
85
Week 16
Quarterly at NIH
3
4
4
10
6
27
112
Week 18
Bi-weekly
3
4
7
119
Week 20
Bi-weekly
3
4
7
126
Week 22
Bi-weekly
3
4
7
133
Week 24
Bi-weekly
3
4
7
140
Week 26
Bi-weekly
3
4
7
147
Week 28
Bi-Quarterly NIH
3
4
4
10
6
27
174
Week 30
Bi-weekly
3
4
7
181
Week 32
Bi-weekly
3
4
7
188
Week 34
Bi-weekly
3
4
7
195
Week 36
Bi-weekly
3
4
7
202
Week 38
Bi-weekly
3
4
7
209
Week 40
Quarterly NIH
3
4
4
10
6
27
236
Week 42
Bi-weekly
3
4
7
243
Week 44
Bi-weekly
3
4
7
250
Study Week
Visit
Hematology (3)
Acute, Hepatic, 
Mineral Panel (4)
Pregnancy 
Testing (4)
Stored Samples 
(10)
Plasma (6)
Total Per Visit 
(mL)
Cummulative Total
(mL)
Week 46
Bi-weekly
3
4
7
257
Week 48
Bi-weekly
3
4
7
264


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Week 50
Bi-weekly
3
4
7
271
Week 52
Quarterly NIH
3
4
4
10
6
27
298
Week 54
Bi-weekly
3
4
7
305
Week 56
Bi-weekly
3
4
7
312
Week 58
Bi-weekly
3
4
7
319
Week 60
Bi-weekly
3
4
7
326
Week 62
Bi-weekly
3
4
7
333
Week 64
Quarterly NIH
3
4
4
10
6
27
360
Week 66
Bi-weekly
3
4
7
367
Week 68
Bi-weekly
3
4
7
374
Week 70
Bi-weekly
3
4
7
381
Week 72
Bi-weekly
3
4
7
388
Week 74
Bi-weekly
3
4
7
395
Week 76
Quarterly NIH
3
4
4
10
6
27
422
Week 78
Bi-weekly
3
4
7
429
Week 80
Bi-weekly
3
4
7
436
Week 82
Bi-weekly
3
4
7
443
Week 84
Bi-weekly
3
4
7
450
Week 86
Bi-weekly
3
4
7
457
Week 88
Quarterly NIH
3
4
4
10
6
27
484
Week 90
Bi-weekly
3
4
7
491
Week 92
Bi-weekly
3
4
7
498
Study Week
Visit
Hematology (3)
Acute, Hepatic, 
Mineral Panel (4)
Pregnancy 
Testing (4)
Stored Samples 
(10)
Plasma (6)
Total Per Visit 
(mL)
Cumulative Total
(mL)
Week 94
Bi-weekly
3
4
7
505
Week 96
Bi-weekly
3
4
7
512
Week 98
Bi-weekly
3
4
7
519
Week 100
Quarterly NIH
3
4
4
10
6
27
546
Week 102
Bi-weekly
3
4
7
553


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Week 104
Bi-weekly
3
4
7
560
Week 106
Bi-weekly
3
4
7
567
Week 108
Bi-weekly
3
4
7
574
Week 110
Bi-weekly
3
4
7
581
Week 112
Quarterly NIH
3
4
4
10
6
27
608
Week 114
Bi-weekly
3
4
7
615
Week 116
Bi-weekly
3
4
7
622
Week 118
Bi-weekly
3
4
7
629
Week 120
Bi-weekly
3
4
7
636
Week 122
Bi-weekly
3
4
7
643
Week 124
Quarterly NIH
3
4
4
10
6
27
670
Week 126
Bi-weekly
3
4
7
677
Week 128
Bi-weekly
3
4
7
684
Week 130
Bi-weekly
3
4
7
691
Week 132
Bi-weekly
3
4
7
698
Week 134
Bi-weekly
3
4
7
705
Week 136
Quarterly NIH
3
4
4
10
6
27
732
Week 138
Bi-weekly
3
4
7
739
Week 140
Bi-weekly
3
4
7
746
Study Week
Visit
Hematology (3)
Acute, Hepatic, 
Mineral Panel (4)
Pregnancy 
Testing (4)
Stored Samples 
(10)
Plasma (6)
Total Per Visit 
(mL)
Cumulative Total
(mL)
Week 142
Bi-weekly
3
4
7
753
Week 144
Bi-weekly
3
4
7
760
Week 146
Bi-weekly
3
4
7
767
Week 148
Quarterly NIH
3
4
4
10
6
27
794
Week 150
Bi-weekly
3
4
7
801
Week 152
Bi-weekly
3
4
7
808
Week 154
Bi-weekly
3
4
7
815
Week 156
Bi-weekly
3
4
7
822
Week 158
Bi-weekly
3
4
7
829


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Study Week
Visit
Hematology (3)
Acute, Hepatic, 
Mineral Panel (4)
Pregnancy 
Testing (4)
Stored Samples 
(10)
Plasma (6)
Total Per Visit 
(mL)
Cumulative Total
(mL)
Week 160
Quarterly NIH
3
4
4
10
6
27
856
Week 162
Bi-weekly
3
4
7
863
Week 164
Bi-weekly
3
4
7
870
Week 166
Bi-weekly
3
4
7
877
Week 168
Bi-weekly
3
4
7
884
Week 170
Bi-weekly
3
4
7
891
Week 172
Quarterly NIH
3
4
4
10
6
27
918
Week 174
Bi-weekly
3
4
7
925
Week 176
Bi-weekly
3
4
7
932
Week 178
Bi-weekly
3
4
7
939
Week 180
Bi-weekly
3
4
7
946
Week 182
Bi-weekly
3
4
7
953
Week 186
Quarterly NIH
3
4
4
10
6
27
980
Week 188
Bi-weekly
3
4
7
987
Week 190
Bi-weekly
3
4
7
994
Week 192
Bi-weekly
3
4
7
1001
Week 194
Bi-weekly
3
4
7
1008
Week 196
Bi-weekly
3
4
7
1015
Week 198
Quarterly NIH
3
4
4
10
6
27
1042
Week 200
Bi-weekly
3
4
7
1049
Week 202
Bi-weekly
3
4
7
1056
Week 204
Bi-weekly
3
4
7
1063
Week 206
Bi-weekly
3
4
7
1070
Week 208
Bi-weekly
3
4
7
1077
Week 210
Quarterly NIH
3
4
4
10
6
27
1104
Week 212
Bi-weekly
3
4
7
1111
Week 214
Bi-weekly
3
4
7
1118
Week 216
Bi-weekly
3
4
7
1125
Week 218
Bi-weekly
3
4
7
1132


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Study Week
Visit
Hematology (3)
Acute, Hepatic, 
Mineral Panel (4)
Pregnancy 
Testing (4)
Stored Samples 
(10)
Plasma (6)
Total Per Visit 
(mL)
Cumulative Total
(mL)
Week 220
Bi-weekly
3
4
7
1139
Week 222
Quarterly NIH
3
4
4
10
6
27
1166
Week 224
Bi-weekly
3
4
7
1173
Week 226
Bi-weekly
3
4
7
1180
Week 228
Bi-weekly
3
4
7
1187
Week 230
Bi-weekly
3
4
7
1194
Week 232
Bi-weekly
3
4
7
1201
Week 234
Quarterly NIH
3
4
4
10
6
27
1228
Week 236
Bi-weekly
3
4
7
1235
Week 238
Bi-weekly
3
4
7
1242
Week 240
Bi-weekly
3
4
7
1240
Week 242
Bi-weekly
3
4
7
1256
Week 244
Bi-weekly
3
4
7
1263
Week 246
Quarterly NIH
3
4
4
10
6
27
1290
Week 248
Bi-weekly
3
4
7
1297
Week 250
Bi-weekly
3
4
7
1304
Week 252
Bi-weekly
3
4
7
1311
Week 254
Bi-weekly
3
4
7
1318
Week 256
Bi-weekly
3
4
7
1325
Week 258
NIH
3
4
4
10
6
27
1352


NIH Intramural Research Program
Office of Human Subjects Research Protections
Effective Date: 07/01/2019
Non-Compliance in Human Subjects Research
Policy 801
Version: 1
Appendix F NIH SOP 801
Policy
1. Purpose
1.1. This policy outlines the requirements for the reporting research-related events to the 
Institutional Review Board (IRB).
2. Scope
2.1. This policy applies to all NIH investigators conducting human subjects research (also 
referred to in this policy as “studies”) and to the Office of Human Subjects Research 
Protections (OHSRP).
2.2. This policy applies to investigators not covered by the NIH FWA when the NIH is the 
Reviewing IRB for human subjects research conducted by these investigators.
3. Policy
3.1. For all human subjects research in which an NIH IRB is the Reviewing IRB, NIH Principal 
Investigators (PIs) and, as applicable, non-NIH Site PIs/Lead Investigators (further referred 
to as non-NIH investigators), are required to ensure that all reportable events, as defined in 
this policy, are reported to the OHSRP office of Compliance and Training within the time 
frames as specified in this policy.
3.1.1. The NIH Principal Investigators (PIs)/designee and, as applicable, non-NIH 
Investigators must report events to the OHSRP office of Compliance and Training via 
the Reportable Event Submission Form (REF) in NIH iRIS in accordance with 
Section 5.1, whether the events occur at the NIH or a non-NIH site;
3.2. For human subjects research when the Reviewing IRB is not an NIH IRB, NIH PIs/Lead 
investigators (further referred to as NIH PI(s) to include NIH PIs, NIH Site PIs in the case 
of multisite research, and NIH AIs participating in a collaborative research protocol with a


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non-NIH PI) are required to ensure that the reporting requirements of the Reviewing IRB 
are followed by NIH staff.
3.2.1. When the Reviewing IRB is a non-NIH IRB, and the event occurred at an NIH site, 
the NIH PI must report the event to the Reviewing IRB in accordance with that IRB’s 
instructions, and also to the OHSRP office of Compliance and Training via the REF 
in NIH iRIS within 7 calendar days of the NIH PI becoming aware of the event;
3.2.2. When the Reviewing IRB is a non-NIH IRB, and the event occurred at a non-NIH 
site, the NIH PI/NIH lead Investigator is required to ensure that the reporting 
requirements of the Reviewing IRB are followed. The investigator does not also 
report these events to the OHSRP office of Compliance and Training.
3.3. Additional reporting may also be required as specified by an NIH Institute/Center (IC) or 
other NIH policy.
3.4. This policy’s reporting requirements are in addition to the requirements of regulatory 
agencies (such as the FDA) and/or any institutionally agreed-upon requirements, e.g., with 
study sponsors or through reliance agreements.
4. Definitions
4.1.Adverse Event (AE) - Any untoward medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in research, whether or not 
considered related to the subject’s participation in the research. In the context of FDA- 
required reporting, an AE means any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related.
4.2. NIH Investigator - An NIH federal employee (intramural or extramural) who is conducting 
human subjects research on behalf of the NIH. Additionally, this designation includes an


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investigator who is not an NIH federal employee but who is conducting human subjects 
research while working at an NIH site with an NIH employee. These researchers may 
include Guest Researchers, Special Volunteers, contractors (subject to the terms of the 
contract), Intramural Research and Cancer Research Training Awardees and colleagues 
from academia and industry who are not Special Government Employees (SGEs) or 
Intergovernmental Personnel Act appointee.
4.3. Non-Compliance - Failure of investigator(s) to follow the applicable laws, regulations, or 
institutional policies governing the protection of human subjects in research, or the 
requirements or determinations of the IRB, whether intentional or not. For the purposes of 
this policy, failure of subjects to comply with the research protocol does not represent non- 
compliance unless that failure is due to an action or omission of a member of the research 
team, for example, the failure to give adequate instruction to the subject.
4.3.1. Serious non-compliance - Non-compliance, whether intentional or not, that results in 
harm or otherwise materially compromises the rights, welfare and/or safety of the 
subject. Non-compliance that materially effects the scientific integrity or validity of 
the research may be considered serious non-compliance, even if it does not result in 
direct harm to research subjects.
4.3.2. Continuing non-compliance - A pattern of recurring non-compliance that either has 
resulted, or, if continued, may result in harm to subjects or otherwise materially 
compromise the rights, welfare and/or safety of subjects, affect the scientific integrity 
of the study or validity of the results. The pattern may comprise repetition of the 
same non-compliant action(s), or different non- compliant events. Such non- 
compliance may be unintentional (e.g. due to lack of understanding, knowledge, or 
commitment), or intentional (e.g. due to deliberate choice to ignore or compromise 
the requirements of any applicable regulation, organizational policy, or determination 
of the IRB).


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4.4. Protocol Deviation (PD) - Any change, divergence, or departure from the IRB-approved 
research protocol.
4.4.1. Major Deviations - Deviations from the IRB approved protocol that have, or may 
have the potential to, negatively impact, the rights, welfare or safety of the subject, or 
to substantially negatively impact the scientific integrity or validity of the study.
4.4.2. Minor Deviations - Deviations that do not have the potential to negatively impact the 
rights, safety, or welfare of subjects or others, or the scientific integrity or validity of 
the study.
4.5. Reportable Event - An event that occurs during the course of human subjects research that 
requires notification to the IRB. For the purposes of this policy, reportable events include 
non-compliance and unanticipated problems involving risks to subjects or others (also 
referred to as UPs), major deviations, deaths related or possibly related to research activities 
and new information that might affect the willingness of subjects to enroll or continue 
participation in the study.
4.6. Reviewing IRB - The IRB responsible for reviewing human subjects research and 
determining that the research meets the required criteria for approval under the HHS 
regulatory requirements at 45 CFR 46 and, as applicable, the pertinent Subparts of 21 CFR.
4.7. Serious Adverse Event (SAE) -is any Adverse Event that:
•
Results in death;
•
Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred);
•
Results in inpatient hospitalization or prolongation of existing hospitalization;
•
Results in a persistent or significant disability/incapacity;
•
Results in a congenital anomaly/birth defect; OR
•
Based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
this definition (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias or convulsions


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that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse).
In IND-regulated research, this term is used synonymously with serious
suspected adverse reaction. (See 21 CFR 312.32(a) for the FDA definition.)
4.8. Unanticipated (Unexpected) - An experience that was not expected or previously observed, 
or is not consistent in nature, severity, or frequency with existing risk information, such as 
in the investigator’s brochure, device manual, research protocol, consent form, or other 
available information (e.g., IND application for an investigational drug or IDE application 
for an investigational device). Interchangeable with “unexpected”. This includes an event or 
problem occurring in one or more subjects in a research study that is not consistent with the 
expected natural progression of any underlying disease, disorder, or condition of the subject 
experiencing the event/problem.
4.9. Unanticipated adverse device effect - means any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in 
the investigational plan or application (including a supplementary plan or application),
or any other unanticipated serious problem associated with a device that relates to the right, 
safety, or
welfare of subjects.
4.10.Unanticipated Problem Involving Risks to Subjects or Others (UP) - Any incident, 
experience, or outcome that meets all the following criteria:
4.10.1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB- 
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; and


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4.10.2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research), and
4.10.3. Suggests that the research places subjects, or others (which may include research 
staff, family members or other individuals not directly participating in the research) at 
a greater risk of harm (including physical, psychological, economic, or social harm) 
related to the research than was previously known or expected.
5. Responsibilities and Requirements
5.1.
Responsibilities of investigators:
5.1.1. The PI must ensure that all AEs and SAEs are appropriately identified, tracked and 
recorded, according to the IRB-approved protocol, data and safety monitoring plan, 
and in accordance with any additional NIH, regulatory, IC-specific and/or study 
sponsor requirements. (Policy 506 Data and Safety Monitoring)
5.1.2. The NIH Principal Investigators (PIs)/designee and, as applicable, non-NIH 
Investigators, must ensure that the following events are reported within the time 
frames specified below. (See Appendix 1: Investigator Reporting Requirements and 
Timeframes for tabular view of these requirements)
5.1.2.1. Non-compliance: Any actual or suspected non-compliance by any 
investigator or entity associated with the protocol must be reported by the 
NIH PI/designee within 7 calendar days of any investigator or individual 
associated with the protocol first becoming aware, unless otherwise indicated 
in this policy. Please refer to policy 802 Non-compliance in Human Subjects 
Research.
5.1.2.1.1. Non-NIH IRB Determinations of serious and/or continuing non- 
compliance about an NIH investigator: If the NIH is relying on a non-NIH 
IRB and the Reviewing IRB makes a determination of serious and/or


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continuing non-compliance regarding an NIH investigator, then, even if the 
determination has already been provided to OHSRP either directly or via 
the NIH Institutional Official (IO)/designee, the NIH PI/designee must 
report this in iRIS within 7 calendar days of any member of the research 
team being notified of the determination by the Reviewing IRB. The NIH 
PI must provide the OHSRP office of Compliance and Training with 
documentation from the Reviewing IRB unless this documentation has 
already been provided directly to the office by the Reviewing IRB or via 
the IO.
5.1.2.2. Major Deviation: A deviation must be reported within 7 calendar days of an 
investigator becoming aware of an actual or suspected deviation. Although 
protocol deviations are also non-compliance, these should only be reported 
once as deviations.
5.1.2.3. Unanticipated Problem (UP): A UP must be reported within 7 calendar days 
of an investigator becoming aware of the actual or suspected UP.
5.1.2.4. Death: Any death of a research subject that is possibly, probably or definitely 
related to the research must be reported within 24 hours of an investigator 
becoming aware of the death.
5.1.2.5. New information that might affect the willingness of a subject to enroll or 
remain in the study should be reported within 7 calendar days of an 
investigator first becoming aware.
5.1.2.6. Any suspension or termination of research activities, including holds on new 
enrollment, placed upon the research by the study sponsor, NIH or IC 
leadership, or any regulatory agency must be reported within 7 calendar days 
of an investigator becoming aware.


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5.1.2.7. Investigators must provide the following information to the IRB in summary 
format at the time of continuing review, or when otherwise specifically 
requested by the IRB or the OHSRP office of Compliance and Training.
5.1.2.7.1. Minor protocol deviations.
5.1.2.7.2. Adverse events and Serious Adverse Events that do not meet the definition 
of an UP.
5.1.3. For FDA regulated studies, investigators are required to report events to the study 
sponsor as described in the protocol and to immediately (i.e., no longer than 10 days) 
report SAEs or UADEs to the study sponsor and, if also an actual or suspected UP, to 
the IRB within 7 calendar days of an investigator becoming aware.
5.2.
Responsibilities of the OHSRP Office of Compliance and Training and the
IRB(s):
5.2.1. When NIH is the Reviewing IRB, the OHSRP office of Compliance and Training is 
responsible for the following:
5.2.1.1. Conducting initial evaluation and triage of all reportable events submitted 
using iRIS.
5.2.1.2. In consultation, as needed, with the OHSRP Director, IRBO Director, and/or 
Executive Chair, determining if any reported event requires immediate action 
to protect the rights, safety or welfare of research subjects and if so, 
communicating such actions to the Principal Investigator and the IRB.
5.2.1.3. Referring potentially serious and/or continuing non-compliance to the 
Research Compliance Review Committee (RCRC).
5.2.1.4. Referring reported UPs to the convened IRB for determination and review of 
any proposed changes to the protocol or consent made by the PI in response 
to the UP.


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5.2.1.5. Reporting to OHRP and, as applicable, FDA, all NIH IRB determinations of 
serious and/or continuing non-compliance, UPs, or NIH IRB suspensions or 
terminations of IRB approval within 30 days of the submission of the 
reportable event and/or will make interim reports in advance of the IRB’s 
final determination as necessary.
5.2.2. When NIH is the Reviewing IRB, the RCRC, as a duly constituted IRB, is responsible 
for the following:
5.2.2.1. Reviewing possible serious and/or continuing non-compliance occurring 
within studies under the NIH IRB’s purview.
5.2.2.2. Determining whether serious and/or continuing non-compliance occurred, 
and evaluating the adequacy of any proposed corrective action. (See Policy 
802 Non-compliance in Human Subjects Research).
5.2.3. For studies in which the reviewing IRB is a non-NIH IRB, the regulatory 
responsibility for reporting to federal agencies lies with the Reviewing IRB unless 
otherwise specified in the reliance agreement.
6. References
6.1.
Federal Regulations
DHHS: 45 CFR 46
FDA: 21 CFR parts 50, 56, 312 and 812
6.2.
NIH Policies
Policy 506 Data and Safety Monitoring
Policy 802 Non-Compliance in Human Subjects Research
6.3.
Guidance
E6(R2) Good Clinical Practice: Integrated Addendum to ICH 
E6(R1):Guidance for Industry
OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving 
Risks to Subjects or Others (2007)
7. Appendices:
7.1.
Appendix 1: Investigator Reporting Requirements and Timeframes


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8. Revision History: N/A
8.1.
Supersedes Date: 07/01/2019
SOP 16 Reporting Requirements for Unanticipated Problems, Adverse Events 
and Protocol Deviations
V.4 dated 3/14/2016 
V.3 dated 2/24/2016
V.4 dated 2/26/14 (form only, note out of order versioning)
V.2 dated 10/01/2013 (form only) 
V.1 dated 6/11/2013
V.1 dated 6/11/2013


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Appendix 1: Principal Investigator/Designee Reporting Requirements and Timeframes
Investigator 
status
NIH IRB is Reviewing IRB
Non-NIH IRB is Reviewing 
IRB
NIH PI, or as 
applicable, the NIH 
lead site 
investigator
• Report the following events to the 
NIH IRB within 7 calendar days of 
any investigator first becoming 
aware*
o
Actual or suspected non- 
compliance 
o
Actual or suspected Major 
deviations 
o
Actual or suspected 
Unanticipated Problems (UPs)
o
New information that might affect 
the willingness of a subject to 
enroll or remain in the study
o
Suspension or termination of 
research activities, including holds 
on new enrollment, placed upon 
the research by the study sponsor, 
NIH or IC leadership, or any 
regulatory agency
• Death of a research subject that is 
possibly, probably or definitely related 
to the research must be reported within 
24 hours of the investigator becoming 
aware of the death
• For FDA regulated studies, report 
events to the study sponsor as 
described in the protocol and 
immediately report (i.e., no longer than 
10 days) SAEs or UADEs to the study 
sponsor and, if also an actual or 
suspected UP, to the IRB within 7 
calendar days of the investigator 
becoming aware.
Report minor deviation and adverse events 
and serious adverse events that are not UPs
• Report events to the 
Reviewing IRB as per 
its policy
• If event occurs at an NIH 
site, also report to the 
Reviewing IRB and the 
OHSRP office of 
Compliance and Training 
within 7 calendar days*
• For FDA regulated 
studies, report events to 
the study sponsor as 
described in the protocol 
and immediately report 
(i.e., no longer than 10 
days) SAEs or UADEs to 
the study sponsor and, if 
also a UP, to the IRB 
within 7 calendar days.
• Report any determinations 
by the non-NIH Reviewing 
IRB of serious and/or 
continuing non-compliance 
by an NIH investigator in 
iRIS within 7 calendar 
days.* Also, provide the 
OHSRP office of 
Compliance and Training 
with documentation from 
the Reviewing IRB unless 
this documentation has 
already been provided 
directly to the office by the 
Reviewing IRB or via the


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at the time of continuing review, or when
otherwise specifically requested by the IRB 
or the OHSRP office of Compliance and 
Training.
Institutional
Official.
Non-NIH
Investigator
Requirements for reporting events to the 
NIH IRB are the same as those for the NIH 
investigators as defined above** (Non-NIH 
investigators should consult their 
institution’s policies if local reporting is also 
required.)
Report events to the Reviewing 
IRB as per its policy
*Submit a Reportable Event Form in iRIS
** Mode of submission by the Non-NIH Investigator will be determined by the IRBO


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Appendix G NIH SOP 802
Policy
A. Purpose
1.
The purpose of this policy is to describe the process for the investigation and 
resolution of allegations of non-compliance.
B. Scope
1.
This policy applies to NIH investigators conducting human subjects research 
reviewed by an NIH IRB.
2.
This policy applies to investigators not covered by the NIH FWA when the 
NIH is the Reviewing IRB for human subjects research conducted by these 
investigators.
3.
This policy applies to the OHSRP and its offices and the NIH IRB.
4.
This policy also applies to persons or entities within the NIH who suspect 
possible non- compliance in the conduct of human subjects research.
C. Policy
1.
NIH investigators are required to follow all applicable laws, regulations, and 
NIH institutional policies governing the protection of human subjects in 
research. Non-NIH investigators who are under the jurisdiction of the NIH 
IRBs, must follow applicable laws, regulations and NIH policies as they 
relate to the protection of human subjects in research.
2.
Investigators, any member or component of the NIH Human Research 
Protection Program (HRPP), or any individual or entity within the NIH who 
suspects possible non-compliance in the conduct of human subjects research, 
is required to report such an occurrence consistent with this policy.
3.
Allegations may be made anonymously and will be investigated to the extent 
possible.
4.
The identity of complainants will be kept confidential to the extent possible.
5.
Allegations from subjects or their family members that relate to possible non-
compliance may also be reported.
6.
All allegations of non-compliance should be reported to the OHSRP office 
of Compliance and Training (see Policy 801 Reporting Research Events).
7.
Allegations of non-compliance will be investigated in a fair and timely 
manner, and the respondent will be given an opportunity to respond to any 
allegation of non-compliance before a final determination is made.
8.
Allegations related to possible non-compliance of an IRB will be referred to 
the Deputy Director for Intramural Research (DDIR) who will determine the 


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process for investigating the allegation.
9.
For all protocols in which the research was conducted under the jurisdiction 
of the NIH IRBs, the Research Compliance Review Committee (RCRC) has 
the final authority to determine whether there is non-compliance and, if so, 
whether it is serious and/or continuing.
10.
When NIH is relying on an external IRB, NIH investigators must follow the 
policies of the Reviewing IRB for reporting possible non-compliance. Please 
see Policy 801 Reporting Research Events for additional NIH reporting 
requirements.
11.
The individual(s) who alleges non-compliance (Complainant) related to 
human subjects research will be informed, upon request, whether the 
investigation is continuing or completed. Additional information will be 
provided consistent with federal law and policy.
12.
Allegations of non-compliance made in good faith will not reflect negatively 
on the reporting individual, nor lead to reprisal against that individual.
D. Definitions
1.
Allegation of Non-Compliance (also “allegations”) - A disclosure of 
possible non- compliance through any means of communication (e.g., by 
written or oral statement) to an NIH official. This may include concerns from 
research participants, investigators, staff, IRB members, reports from audits, 
and discoveries made during review of other human subjects issues, such as 
protocol deviations. It does not include self-reporting by the PI/designee to 
the IRB, using a reportable event form submitted in iRIS.
2.
Complainant - A person who makes an allegation of non-compliance.
3.
NIH Investigator - An NIH federal employee (intramural or extramural) who 
is conducting human subjects research on behalf of the NIH. Additionally, 
this designation includes an investigator who is not an NIH federal employee 
but who is conducting human subjects research while working at an NIH site 
with an NIH employee. These researchers may include Guest Researchers, 
Special Volunteers, contractors (subject to the terms of the contract), 
Intramural Research and Cancer Research Training Awardees and 
colleagues from academia and industry who are not Special Government 
Employees (SGEs) or Intergovernmental Personnel Act appointee.
4.
Non-Compliance - Failure of investigator(s) to follow the applicable laws, 
regulations, or institutional policies governing the protection of human 
subjects in research, or the requirements or determinations of the IRB, 
whether the failure is intentional or not. For the purposes of this policy, 
failure of subjects to comply with the research protocol does not represent 
non- compliance unless that failure is due to an action or omission of a 
member of the research team, for example, the failure to give adequate 
instruction to the subject.

Serious non-compliance - Non-compliance, whether intentional or not, 
that results in harm or otherwise materially compromises the rights, 
welfare and/or safety of the subject. Non-compliance that materially 
affects the scientific integrity or validity of the research may be 
considered serious non-compliance, even if it does not result in direct 
harm to research subjects.


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
Continuing non-compliance - A pattern of recurring non-compliance that 
either has resulted, or, if continued, may result in harm to subjects or 
otherwise materially compromise the rights, welfare and/or safety of 
subjects, affect the scientific integrity of the study or validity of the 
results. The pattern may comprise repetition of the same non- compliant 
action(s), or different non-compliant events. Such non- compliance may 
be unintentional (e.g. due to lack of understanding, knowledge, or 
commitment), or intentional (e.g. due to deliberate choice to ignore or 
compromise the requirements of any applicable regulation, 
organizational policy, or determination of the IRB).
5.
(The) OHSRP office of Compliance and Training - The component of 
OHSRP responsible for review, management, and required reporting of 
problems occurring during the conduct of IRP human subjects research 
(HSR). This component also conducts non-compliance inquiries as well as 
QA/QI Reviews of NIH IRBs. This component also provides education and 
training related to human subjects protections, IRB policies and procedures 
for HRPP investigators, research staff, and the NIH IRB.
6.
Reliance Agreement - An agreement between the NIH and one or more sites 
involved in the same cooperative research that assigns IRB regulatory 
responsibilities to a specified IRB. This is sometimes referred to as an IRB 
Authorization Agreement.
7.
Research Compliance Review Committee (RCRC) - A duly established NIH 
IRB that adheres to the membership and committee requirements described 
in Policy 302-IRB Membership and Composition and Policy 402-IRB 
meetings. The RCRC primarily reviews allegations of non-compliance that 
have been deemed by the office of Compliance and Training to be both 
credible and potentially serious and/or continuing. As a duly convened 
committee, the RCRC may exercise the full authority of an IRB including 
suspension or termination of IRB approval of research.
8.
Respondent - The investigator or entity, if any, against whom an allegation 
of non- compliance is made.


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E. Responsibilities and Requirements
1.
Investigators are required to follow all applicable laws, regulations, and NIH 
institutional policies governing the protection of human subjects in research. 
Non-NIH investigators who are under the jurisdiction of the NIH IRB, must 
follow applicable laws, regulations and NIH policies as they relate to 
governing the protection of human subjects in research.
2.
Additionally, any member or component of the NIH Human Research 
Protection Program (HRPP), or any individual or entity within the NIH who 
suspects possible non- compliance in the conduct of human subjects 
research, is required to report such an occurrence. This must be reported in a 
timely manner to the office of Compliance and Training.
3.
The Respondent and any involved person or entity are expected to fully 
cooperate with any investigation of non-compliance and provide any 
requested information and/or materials to the office of Compliance and 
Training, the IC, NIH Office of the Director (OD), or any other authorized 
party.
4.
When an NIH IRB is the Reviewing IRB, the office of Compliance and 
Training is responsible for conducting the preliminary review of allegation 
of non-compliance, in consultation with, as necessary, the OHSRP Director, 
IRBO Director and/or the Executive Chair.
a.
The office of Compliance and Training will make a preliminary 
determination for the HRPP as to whether the allegation is credible 
(e.g., has a basis in fact) and falls within the scope of human subjects 
protections and, if so, whether the allegation of non-compliance, if 
true, is potentially serious and/or continuing.
I.
If allegations meet these criteria, the respondent will be notified 
of the allegations. The office of Compliance and Training will 
refer allegations of non-compliance deemed by it to be 
potentially serious and/or continuing to the RCRC. This will 
occur whether the protocol is open or not at the time of the 
allegation.
II.
If the answer to any of these criteria is “no,” then the investigation 
will not proceed to consideration by the RCRC and the respondent 
will be notified.
III.
Possible non-compliance relating to concerns outside the scope 
of human subjects protections may be referred to the appropriate 
office for further review (e.g. matters related to possible 
scientific misconduct will be forwarded to the NIH Agency 
Intramural Research Integrity Officer (AIRIO)).
b.
In consultation with the OHSRP Director, IRBO Director and/or the 
Executive Chair, the office of Compliance and Training is 
responsible for determining for OHSRP if immediate steps are 
necessary to protect the rights, welfare and safety of subjects and 
communicate this to the RCRC and the PI.
I.
Administrative holds may also be placed on the research by the 
study sponsor, OD or NIH Institute or Center (IC) leadership, or 
any regulatory agency.
5.
The RCRC is responsible for reviewing possible serious or continuing non- 
compliance in human subjects research for which an NIH IRB is the 
Reviewing IRB that has been referred from the office of Compliance and 


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Training. The RCRC has the final authority to determine whether there is 
non- compliance that is serious and/or continuing and to determine corrective 
action.
a.
On behalf of the RCRC, the office of Compliance and Training is 
responsible for coordinating any investigation of an allegation of non- 
compliance, in consultation with the Director of OHSRP, the Director 
of IRBO and/or the Executive Chair of the NIH IRB. Additional 
resources will be requested from the HRPP and IC leadership as 
needed.
b.
A written report will be prepared by office of Compliance and 
Training describing the possible non-compliance, evidence examined, 
and summary or source documents (if pertinent) of the investigation. 
The report will be provided to the RCRC and the respondent.
c.
The respondent will be provided an opportunity to address the RCRC 
in person if they so choose and/or provide a written response.
d.
The RCRC will make the final determination regarding non- 
compliance and if it is serious and/or continuing. The determination


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will be provided in writing to the respondent, as well as to the Director 
OHSRP, IRBO Director, the DDIR, and the relevant IC CD.
I.
When the NIH IRB(s) is the Reviewing IRB for a multi-center 
study, reporting to non-NIH sites will be governed by the terms 
of the reliance agreement.
e.
As appropriate, the investigator with assistance of their IC, as needed, 
will initiate corrective action.
I.
As part of its deliberations, the RCRC will determine the 
adequacy of any proposed corrective actions.
II.
As a duly convened IRB, the RCRC may require modifications 
to any proposed corrective action as a condition for continued 
approval of research, for example, continued monitoring, 
notification to past research subjects, or reconsent of current 
subjects when the investigation results in information that might 
impact the subjects’ willingness to continue participation. (45 
CFR 46.116(b)(5) (pre-2018 Common Rule) or 45 CFR 
46.116(c)(5) (2018 Common Rule), and 21 CFR 50.25(b)(5) as 
applicable).
f.
As a duly convened committee, the RCRC may exercise the full 
authority of an IRB including suspension or termination of IRB 
approval of research (see Policy 402 NIH IRB Meetings).
g.
The office of Compliance and Training will report to appropriate 
regulatory authorities and institutional officials as described in Policy 
801 Reporting Research Events.
h.
An investigator may request reconsideration by the RCRC of a finding 
of serious and/or continuing non-compliance for good cause, such as 
submission of new information that was not considered or available 
during the investigation, material failure to follow the non-compliance 
policies, or that the corrective action(s) is perceived to exceed the 
severity of the non-compliance.
i.
Requests for reconsideration will be submitted in writing to the 
Director of OHSRP for consideration, who has final authority to 
determine if the finding will be reconsidered by the RCRC.


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6.
When the NIH is relying on an external Reviewing IRB, any allegations of 
possible non- compliance received by the office of Compliance and Training 
that have not already been reported to the Reviewing IRB will be 
communicated to the Reviewing IRB based on that IRB’s reporting 
requirements.
a.
The office of Compliance and Training will coordinate with the 
Reviewing IRB, with input from the OHSRP Director, the IRBO 
Director and/or the NIH Executive Chair, regarding any investigation 
of an allegation of non-compliance involving an NIH investigator.
b.
The Reviewing IRB has final regulatory authority to determine if the 
non- compliance is serious and/or continuing, unless otherwise 
specified in the terms of the reliance agreement.
c.
NIH will work with the Reviewing IRB in developing corrective 
action as needed to assist with resolution of the problem
d.
If the Reviewing IRB determines the non-compliance to be serious 
and/or continuing, the office of Compliance and Training will report to 
the appropriate NIH officials as required by Policy 801-Reporting 
Research Events.
e.
The policies of the Reviewing IRB will apply to the appeal of any 
determinations of serious and/or continuing non-compliance, unless 
otherwise specified by the terms of the reliance agreement.
7.
The IC leadership or other institutional authorities, such as the Institutional 
Official, have the authority to take restrictive measures above and beyond 
what has been required by the Reviewing IRB including, stopping research 
activities, closure of the protocol, or other actions within the scope of its 
authority (see Policy 102 NIH's Human Research Protection Program 
(HRPP) and Policy 103 Organizational Structure of the OHSRP).
8.
At the conclusion of the investigation, the office of Compliance and Training 
will notify the complainant consistent with federal law and policy.


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F. References
1.
Federal Regulations 
HHS: 45 CFR 46 
FDA: 21 CFR
2.
NIH Policy
Policy 102 NIH's Human Research Protection Program (HRPP) Policy 
103 Organizational Structure of the OHSRP
Policy 302 IRB Membership and Composition Policy 402 IRB 
Meetings;
Policy 801 Reporting Research Events
3.
Guidance: NA
G. Appendices: None
H. Revision History: NA
I.
Supersedes Date: 07/01/2019
SOP 16A Allegations of Non-compliance with Requirements of the NIH 
Human Research Protection Program (HRPP), versions:
V. 3, dated 03-17-2016
V. 2, dated 10-01-2013
V.1, dated 6-11-2013

ICF_000.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/29/2021
Page 1 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Alexandra Freeman, MD
STUDY TITLE: 
A Phase IIa Efficacy, Safety, Tolerability and Pharmacokinetic 
Study of Encochleated Amphotericin B (CAMB) in Patients with 
Mucocutaneous (Esophogeal, Oropharyngeal, Vaginal) Candidiasis 
Who are Refractory or Intolerant to Standard Non-Intravenous 
Therapies
STUDY SITE:
NIH Clinical Center
Cohort:  Affected Patient
Consent Version:  March 29, 2021 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Alexandra Freeman , MD  freemaal@mail.nih.gov   301/594/9045
Study Coordinator: Doris Swaim, RN                     doris.swaim@nih.gov      301/827/9716
 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
You are participating in a study of an experimental antifungal drug called encochleated 
amphotericin B (or CAMB) to see if it is safe and if it will help treat persistent fungal infections. 
CAMB is a special oral form of the antifungal drug amphotericin B, which is a commonly used 
antifungal treatment. However, the traditional form of amphotericin B can only be given 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/29/2021
Page 2 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
intravenously and also has been known to have some severe side effects. We want to see if this 
new oral form of amphotericin B will be safe for treating fungal infections without some of these 
side effects.
You already agreed to participate in this study and the optional extension period to receive CAMB 
for a total of 48 months. We are inviting you to continue the extension period for a total of 
60 months of treatment with CAMB.
For this study, the NIH is partnering with the maker of CAMB, a company called Matinas 
Biopharma Nanotechnologies, Inc.. CAMB has not been approved by the US Food and Drug 
Administration (FDA) for use in humans, but the FDA has given us permission to use it in this 
study. CAMB has also been tested in 47 healthy human volunteers at the same doses we will use 
in this study, however those participants only received one single dose.  
EXTENSION SCHEDULE
In the extension, you may continue taking CAMB for up to 60 months. During this period of time, 
we will see you at least every 12 weeks at the NIH Clinical Center (CC). We may see you more 
frequently if you are having any side effects. At these visits, we will do the following procedures:
•
Blood and urine tests to look for any side effects.
•
Pregnancy tests (if you are able to get pregnant).
•
Swabs for fungal cultures.
•
A clinical evaluation and physical exam (including a gynecologic exam if your infection is 
in your vagina).
•
Optional collection of blood, urine, saliva, stool and vaginal secretions for research tests 
and storage for future research.
•
Clinical photography of your infection, if applicable.
Between the 12-week visits to the NIH, we will have you get blood work checked every 2 weeks 
to look for side effects. The 2-week blood draws can be done at your community laboratory. Also, 
we will call you every 2 weeks in between the 12-week visits to ask about any new symptoms or 
medications. 
Some visits can be replaced with phone or computer calls with the study doctors to discuss how 
CAMB is making you feel and if you have had any side effects. You can visit your local clinical 
laboratory (such as Quest Diagnostics or LabCorp) or your primary care doctor, who can collect 
your blood and urine samples and send the results of the tests to us. Your sample will be labeled 
with a coded study identifier (Matinas MB70004), gender and date of birth. The local clinical lab 
charges will be billed to the study sponsor. We will let you know which visits can be done this 
way.
You need to avoid becoming pregnant for the duration of your participation. If you become 
pregnant while on this study or during the 4 weeks after your last dose of the study medication, 
then you need to inform the study doctors as soon as possible. You will be asked to stop taking 
CAMB, but the study doctors will continue to follow up with you for safety and pregnancy 
outcome.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/29/2021
Page 3 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If during the study you engage in sexual activities that could cause pregnancy, the following forms 
of pregnancy prevention are acceptable: 
•
Have had a hysterectomy and/or had both tubes tied (bilateral tubal ligation) or both 
ovaries removed.
•
Be in a monogamous relationship with a partner who has had a vasectomy at least 
6 months ago.
•
Have an intra-uterine device (IUD).
•
Be on birth control pills, patch, ring, implant, or injection, and 
•
If you use the pill, patch, or ring then you must also use a condom, cap, or diaphragm 
with spermicide.
STUDY PROCEDURES
Clinical evaluation and physical exam
We will assess your infection to determine its severity and if it is responding to the investigational 
treatment. You will have a physical exam, which includes taking your temperature, blood pressure, 
respiratory rate, and pulse. We will ask you about how you’re feeling, if you’ve had any illness 
recently, and about the medications you are taking now and have taken in the past, including 
non-prescription drugs. You must tell the study team about all of the medications you are taking 
because you cannot use amphotericin B while taking CAMB. We will discuss each drug with you 
and tell you if it is permitted on the study. For example, you cannot take azole antifungal drugs if 
you are using them to treat your mucocutaneous candidiasis. If you are using an azole antifungal 
drug for some other infections, you may be able to continue. Please also be sure to let the study 
team know about any new medications before you start taking them.
Blood draw
We will draw blood from a vein in your arm to count your blood cells, see if your organs are 
working well, and determine how your body is processing the drug. At some of the study visits, 
we will insert an IV line into a vein in your arm so blood can safely and comfortably be drawn 
throughout the day. 
The amount of blood drawn at each visit to the NIH will be about 2 tablespoons (27 milliliters). 
The amount drawn every 2 weeks between NIH visits will be about half a tablespoon (7 milliliters). 
The total amount at all visits is within the limits allowed by the NIH CC for research purposes. 
While in the study, let the study team know if you are participating in other studies or have blood 
drawn for any other reason. Some of your blood will be stored for possible future testing.
Urine Collection
Urine will be collected into cups for routine medical tests and to determine how CAMB is 
eliminated through urine.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/29/2021
Page 4 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Saliva Collection
You will spit into a tube to collect saliva samples. This is optional, so you may decline this 
procedure and still remain in the study. We will use these samples to see how your body is 
processing CAMB. 
Stool Collection
Collection of your stool is optional so you may decline this procedure and still remain in the study. 
You will pass stool into a plastic container that fits in the toilet under the seat, and then we will 
scoop a little bit into a special tube. We will use your stool to look at how your body is processing 
CAMB.
Vaginal Fluid Collection
If you have an infection in the vaginal area we will ask to take samples of vaginal fluid. This is 
optional, so you may decline this procedure and still remain in the study. Vaginal fluid will be 
collected using a menstrual cup. The study staff will instruct you how and when to insert and 
remove the cup during your study visits. Patients who have an IUD, are on their menstrual period, 
or have had a hysterectomy with removal of the cervix will not need to undergo this procedure. 
We will use your vaginal fluid to look at how your body is processing CAMB.
Gynecological Examination
If your infection is in your vagina, gynecological examinations will be done. We will evaluate the 
skin surrounding the vaginal and pubic area. We will insert a speculum into your vagina and gently 
rub a sterile cotton swab (like a Q-tip) on the infected area so we can look closely at your infection 
in the laboratory.
Fungal Culture Swab
We will gently rub a sterile cotton swab (like a Q-tip) on the infected area of your body so we can 
look closely at your infection in the laboratory. This will help us to better understand how CAMB 
is affecting your infection.
Pregnancy Test
You will have routine blood pregnancy tests during the length of your treatment.
Clinical Photography
We may take pictures of your infection. You will be asked to sign a standard NIH photography 
consent form if you are willing to let us take pictures.
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Consent to Participate in a Clinical Research Study
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
RISKS AND DISCOMFORTS
The likelihood and severity of risks with this study are partially determined by your age, fungal 
infection, overall health, and the medications you use. 
CAMB
A single dose of CAMB was given to healthy volunteers in another research study. In that study, 
commonly reported side effects were nausea and abdominal pain. Other less common side effects 
were vomiting and diarrhea. These side effects were likely the result of volunteers drinking a large 
volume of CAMB to get the full dose. To try to avoid this problem, you will take half of your dose 
twice per day so that each day you get the full dose, but in smaller volumes. There was also one 
case of a moderate respiratory infection that was determined to not be related to CAMB.
Amphotericin B that is injected into the blood and not given orally like CAMB has its own risks. 
These risks include allergic reactions, changes to blood clotting, anemia, gastrointestinal distress, 
and kidney damage. These effects have not been seen in people given one oral dose of CAMB, but 
taking the drug twice a day for several weeks will potentially increase the risk of events that have 
not been seen in other studies.
It is possible that the exposure to CAMB may cause resistance of the Candida to amphotericin. 
This could potentially make intravenous amphotericin less effective as a treatment option if needed 
in the future. After the study, there are other possible treatments that could be used for most 
Candida species if there is amphotericin resistance and an antifungal is needed, and these can be 
discussed with your physician or the study physician. 
There are likely to be other risks to oral CAMB that are unknown, and that is why we will be 
following you closely throughout this study.
Blood Draw
Blood draws may cause pain and bruising and, rarely, infection. Sometimes drawing blood causes 
people to feel lightheaded or even faint.
Vaginal Fluid Collection
The only risk associated with the use of a menstrual cup is the possibility of dislodging an IUD. 
Therefore, if you have an IUD then we will not collect vaginal fluid from you.
Clinical Digital Photography
Taking pictures of the face and body may be embarrassing to some people. These photographs 
may be published in medical journals, without identifying the participant. We will attempt to 
preserve the anonymity of the participant as much as possible, while providing the information 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
needed to support the research being published. You may decline photographs or place restrictions 
on their use. We invite you to talk with us about any concerns you have related to photography.
Urine, Swab, Saliva and Stool Collection
There are no risks associated with collection of urine, swabs, saliva or stool.
BENEFITS OF PARTICIPATION IN THIS STUDY
You may not benefit directly from participating in this study, or your condition could worsen. 
CAMB may help to improve your mucocutaneous candidiasis infection, but it may not, and any 
improvement may end when the study is over. The information we obtain in this study will help 
us learn more about the use of CAMB in treating people with persistent fungal infections.
You will not receive any more CAMB after you have taken your final dose. Because CAMB is 
still under investigation, further approval from the FDA and the NIH Institutional Review Board 
are needed before CAMB can be provided outside of this study.
ALTERNATIVES TO PARTICIPATION IN THIS STUDY
You can choose not to continue to participate in this study and to remain on your current treatment 
plan. This decision will not affect any ongoing care or evaluations you may be receiving at the 
NIH. Your eligibility to participate in other research studies at the NIH will not be affected by your 
decision to enroll or not enroll in this protocol. You may also discuss alternative treatment options 
with your care provider.
WITHDRAWAL FROM THE STUDY
You can stop participating in this study at any time. Tell a member of the study team if you no 
longer want to participate. This decision will not affect any ongoing care or evaluations you may 
be receiving at the NIH.
Samples and data collected prior to this request will be stored for the duration of the protocol 
unless you specifically request the removal of all your samples from the study. 
REASONS FOR ENDING YOUR PARTICIPATION EARLY
You may be removed from the study without your consent if the study doctor feels it is in your 
best interest or if the study is cancelled or stopped early.
 
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
You will not receive any payment for taking part in this extension study.
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
 
Will you receive reimbursement or direct payment by NIH as part of your participation?
For inpatient visits NIH will directly cover travel to and from the CC within the U.S., lodging and 
meals. For outpatient visits NIH will directly cover travel to and from the CC within the U.S. and 
lodging. The agency making the reservations and their representatives will have access to your 
identifiable information. You will receive a $10 meal voucher for the day of your visit. 
When NIH studies offer reimbursement or direct payment for travel and meals related to 
participation in research, your social security number (SSN) is usually collected for the purpose 
of providing payment. Should you choose not to provide your SSN, you may be able to 
participate in the study, but you would not receive any eligible payment. Please note that when 
sharing your SSN, you should not provide your SSN via unsecure methods (regular, unencrypted 
email is an unsecure method) – it is best to provide your SSN in person or to a known person via 
telephone.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH CC. The costs for any other medical care provided outside the 
NIH during this period will not be covered. The local clinical lab charges for this study will be 
billed to the study sponsor.
STORED SAMPLES AND FUTURE RESEARCH
If you agree to participate in this study, then you also agree to let us store some of your blood, 
stool, saliva and vaginal secretions samples for future research. These stored samples may help us 
learn more about mucocutaneous candidiasis. Genetic testing will not be performed. We will label 
your stored samples with a code that only the study team can link to you. We will keep any 
information that can be traced back to you as private as possible. If you change your mind and 
decide you do not want us to store your samples, then please contact us. We will do our best to 
comply with your request but cannot guarantee that we will always be able to destroy all of your 
samples.
We might send your samples to other investigators for their research, along with the coded label. 
We might also share information such as your sex, age, health history, or ethnicity. We will not 
sell your samples and you will not be paid for any products that result from the research. Some 
future studies may need health information (such as smoking history or present health status) that 
we don’t already have. If so, then our study team will contact you. Future research that uses your 
samples will probably not help you, but it may help us learn more about how to treat 
mucocutaneous candidiasis. In general, the research tests we perform are not like routine medical 
tests, and may not relate directly to your medical care. The greatest risk of allowing us to store 
your samples is an unplanned release of your identification from the samples due to release of this 
information from the stored sample database. The chances of this happening are very low.
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Consent to Participate in a Clinical Research Study
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
NEW FINDINGS
Any new findings discovered during this study that are considered relevant to your health or to 
your decision to continue in the study will be fully discussed with you.
CONFLICT OF INTEREST
The NIH reviews NIH staff researchers at least yearly for conflicts of interest. This process is 
detailed in a COI Guide. You may ask your research team for a copy of the COI Guide or for more 
information. Members of the research team who do not work for NIH are expected to follow these 
guidelines or the guidelines of their home institution, but they do not need to report their personal 
finances to the NIH.
The NIH and the research team for this study are using CAMB, a drug developed by Matinas 
Biopharma Nanotechnologies, Inc. through a collaboration between your study team and the 
company. The company also provides financial support for this study. Matinas Biopharma 
Nanotechnologies, Inc. plans to use the results, and may get patents, or sell the drug in the future, 
or make profits other ways. This means it is possible that the results of this study could lead to 
payments to NIH. By law, the government is required to share such payments with the employee 
inventors. You will not receive any money from the development of CAMB.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
We will keep your study information private. All files with information that could identify you 
will be kept in locked cabinets or password-protected, encrypted, and secure computers. In the 
future, some of your information may continue to be stored with a code and not your name. Only 
the study investigator can link that information together.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:
•
The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.
•
National Institutes of Health Intramural Institutional Review Board.
•
The study Sponsor Matinas Biopharma Nanotechnologies, Inc. 
•
Qualified representatives from Matinas Biopharma Nanotechnologies, Inc. 
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Consent to Participate in a Clinical Research Study
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act. In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality. For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
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Consent to Participate in a Clinical Research Study
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
involved in a lawsuit. However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Dr. Alexandra 
Freeman, Building 10, Room 11N234, Telephone (301) 594-9045. Other researchers you may call 
are: Study Coordinator, Doris Swaim, RN Building 10, Room 2C 132B, Telephone (301) 827-
9716.
You may also call the NIH Clinical Center Patient Representative at 301-496-2626, or the NIH 
Office of IRB Operations at 301-402-3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
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