Double-Blind, Randomized, Placebo-Controlled Trial of AKST4290 for Adjunctive Treatment of Mild to Moderate Bullous Pemphigoid
Phase: PHASE2
Conditions: Pemphigoid, Bullous
Sponsor: Alkahest, Inc.



 
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5.2 
EXCLUSION CRITERIA ...................................................................................................... 20 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ............................................. 21 
5.4 
SUBJECT WITHDRAWAL .................................................................................................. 21 
5.4.1 
REASONS FOR WITHDRAWAL ........................................................................................... 21 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS .............................................................. 22 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................... 22 
6 
STUDY AGENTS ................................................................................................................... 22 
6.1 
STUDY AGENT AND CONTROL DESCRIPTION .......................................................... 22 
6.1.1 
ACQUISITION ......................................................................................................................... 22 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING ................................. 23 
6.1.3 
PRODUCT STORAGE AND STABILITY.............................................................................. 23 
6.1.4 
DOSING AND ADMINISTRATION ...................................................................................... 23 
6.2 
STUDY AGENT ACCOUNTABILITY................................................................................ 23 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................... 24 
7.1 
STUDY PROCEDURES/EVALUATIONS .......................................................................... 24 
7.1.1 
STUDY SPECIFIC PROCEDURES ........................................................................................ 24 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ........................................................... 29 
7.2.1 
CLINICAL LABORATORY EVALUATIONS ....................................................................... 29 
7.2.2 
OTHER TESTS OR PROCEDURES ....................................................................................... 29 
7.3 
STUDY SCHEDULE .............................................................................................................. 30 
7.3.1 
SCREENING ............................................................................................................................ 30 
7.3.2 
BASELINE ............................................................................................................................... 31 
7.3.3 
TREATMENT .......................................................................................................................... 31 
7.3.4 
FOLLOW-UP............................................................................................................................ 34 
7.3.5 
EARLY WITHDRAWAL ........................................................................................................ 34 
7.3.6 
TRIAL COMPLETION AND END OF TRIAL ....................................................................... 34 
7.3.7 
SCHEDULE OF EVENTS TABLE .......................................................................................... 34 
7.4 
CONCOMITANT MEDICATIONS ..................................................................................... 34 
 
 
8 
ASSESSMENT OF SAFETY ................................................................................................ 35 
8.1 
SPECIFICATION OF SAFETY PARAMETERS .............................................................. 35 
8.1.1 
DEFINITION OF ADVERSE EVENTS .................................................................................. 35 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS ................................................................. 36 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ................................................................ 37 
8.2.1 
SEVERITY OF EVENT ........................................................................................................... 37 
8.2.2 
RELATIONSHIP TO STUDY AGENT ................................................................................... 37 
8.2.3 
EXPECTEDNESS .................................................................................................................... 37 

 
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8.3 
TIME PERIOD/FREQUENCY FOR EVENT ASSESSMENT/FOLLOW-UP ................ 38 
8.3.1 
POST-STUDY AE AND SAE .................................................................................................. 38 
8.4 
REPORTING PROCEDURES .............................................................................................. 38 
8.4.1 
ADVERSE EVENT REPORTING ........................................................................................... 38 
8.4.2 SERIOUS ADVERSE EVENT REPORTING ............................................................................... 39 
 
 
8.4.4 
REPORTING OF PREGNANCY ............................................................................................. 41 
8.5 
STUDY HALTING RULES ................................................................................................... 41 
8.6 
SAFETY OVERSIGHT ......................................................................................................... 42 
9 
CLINICAL MONITORING ................................................................................................. 42 
10 
STATISTICAL CONSIDERATIONS .................................................................................. 42 
10.1 
STATISTICAL DESIGN MODEL AND ANALYTICAL PLANS .................................... 42 
10.2 
STATISTICAL HYPOTHESES ........................................................................................... 42 
10.3 
ANALYSIS DATASETS ........................................................................................................ 42 
10.4 
DESCRIPTION OF STATISTICAL METHODS ............................................................... 43 
10.4.1 
GENERAL APPROACH .......................................................................................................... 43 
10.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT ........................................................................ 43 
10.4.3 
ANALYSIS OF THE SECONDARY ENDPOINTS ................................................................ 43 
10.4.4 
PLANNED INTERIM ANALYSES ......................................................................................... 44 
10.4.5 
MULTIPLE COMPARISON/MULTIPLICITY ....................................................................... 44 
10.4.6 
EXPLORATORY ANALYSES ................................................................................................ 44 
10.5 
SAMPLE SIZE........................................................................................................................ 45 
10.6 
MEASURES TO MINIMIZE BIAS ...................................................................................... 45 
10.6.1 
ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES ...................................... 45 
10.6.2 
EVALUATION OF SUCCESS OF BLINDING ...................................................................... 45 
10.6.3 
BREAKING THE STUDY BLIND/SUBJECT CODE ............................................................ 45 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............ 45 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS........................................................... 46 
12.1 
ETHICAL STANDARD ......................................................................................................... 46 
12.2 
INSTITUTIONAL REVIEW BOARD ................................................................................. 46 
12.3 
INFORMED CONSENT PROCESS .................................................................................... 46 
12.3.1 
CONSENT FORMS .................................................................................................................. 46 
12.3.2 
CONSENT PROCEDURES AND DOCUMENTATION ........................................................ 46 
12.4 
PARTICIPANT AND DATA CONFIDENTIALITY.......................................................... 47 

 
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17.9 
PHARMACOKINETIC MEASURES AND EVALUATION ............................................ 69 
17.9.1 
TIMING OF PHARMACOKINETIC BLOOD SAMPLING ................................................... 69 
17.9.2 
PHARMACOKINETIC SAMPLE HANDLING AND SHIPMENT ....................................... 69 
17.9.3 
PHARMACOKINETIC DATA EVALUATION ..................................................................... 69 
17.9.4 
HANDLING OF MISSING BIOANALYTICAL DATA ......................................................... 69 
18 
REVISION HISTORY ........................................................................................................... 70 
18.1 
SUMMARY OF CHANGES .................................................................................................. 70 
 
 
 
 

 
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LIST OF ABBREVIATIONS 
AE(s) 
Adverse Event(s) 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine Amino Transferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Amino Transferase 
AUC 
Area under the Curve 
b.i.d. 
Twice Daily 
BP 
Bullous Pemphigoid 
BPDAI 
Bullous Pemphigoid Disease Area Index 
BPDAI-VAS 
Bullous Pemphigoid Disease Area Index Visual Analog Scale 
BLQ 
Below the Limit of Quantification 
CBC 
Complete Blood Count 
 
 
CFR 
Code of Federal Regulations 
CI(s) 
Confidence Interval(s) 
Cmax 
Maximum Plasma Concentration 
CMP 
Clinical Monitoring Plan 
CPC 
Clobetasol Propionate Cream 
CRF 
Case Report Form 
CRO(s) 
Contract Research Organization(s) 
CS(s) 
Corticosteroid(s) 
 
 
DILI 
Drug Induced Liver Injury 
DLQI 
Dermatology Life Quality Index 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
 
 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic Acid 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicine Agency 
EOT 
End of Treatment 
 
 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HEV 
Hepatitis E Virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Council for Harmonisation 
ICH E6 R2 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance, Revision 2 

 
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IEC 
Independent Ethics Committee 
IFN-g 
Interferon-gamma 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IHC 
Immunohistochemistry 
IL 
Interleukin 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat 
MCI 
Mild Cognitive Impairment 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Drug Regulatory Activities  
MFC 
Mometasone Furoate Cream 
MoCA 
Montreal Cognitive Assessment 
NOA 
Not Analyzed 
NOP 
No Peak Detectable 
NOR 
No Valid Result 
NOS 
No Sample Available 
NTI 
Narrow Therapeutic Index 
OVA 
Ovalbumin 
P-gp 
Permeability Glycoprotein 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
QA 
Quality Assurance 
QT 
QT Interval on ECG 
SAE(s) 
Serious Adverse Event(s) 
SAP 
Statistical Analytical Plan 
SOC 
Standard of Care 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
ULN 
Upper Limit of Normal 
VCA 
Vascularized Composite Allotransplantation 
 
 
 

 
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STATEMENT OF COMPLIANCE 
 
Protocol Title: 
Double-Blind, Randomized, Placebo-Controlled Trial of 
AKST4290 for Adjunctive Treatment of Mild to Moderate 
Bullous Pemphigoid 
Protocol Number: 
AKST4290-221 
Version/Date: 
V4.0 15MAY2020 
 
By my signature, I: 
• 
Confirm that my staff and I have carefully read and understand this protocol or protocol amendment, 
have received the Investigator Brochure, and are thoroughly familiar with the appropriate use of the 
investigational agent described herein. 
• 
Agree to comply with the conduct and terms of the study specified herein and with any other study 
conduct procedures provided by the Sponsor, Alkahest, Inc., or their designee. 
• 
Agree to assume responsibility for the proper conduct of the study at this site, including complying with 
current relevant versions of the US Food and Drug Administration (FDA) regulations, European 
Medicines Agency (EMA), the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines, the Declaration of 
Helsinki, and all applicable rules, regulations, and federal, state, and local laws relating to the conduct 
of clinical studies and the protection of human subjects. 
• 
Agree not to implement deviations from or changes to the protocol or protocol amendments without 
agreement from the Sponsor and prior submission to and written approval (where required) from the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except when necessary to 
eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where 
permitted by all applicable regulatory requirements). 
• 
Agree to onsite monitoring of all source documents by Alkahest, Inc. or designee and to onsite 
inspection of source documents by appropriate regulatory authorities, including but not limited to the 
FDA, EMA, local governing regulatory bodies, and IRB/IEC inspectors. 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Print Name 
 
 

 
 
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(DLQI). Additional biomarker evaluations may be conducted on plasma 
samples. 
Endpoints: 
Primary Endpoints: 
• 
The proportion of subjects who achieve disease control (≤ 3 new 
blisters/day and healing of existing blisters) without requiring rescue 
therapy. 
 
Secondary Endpoints: 
• 
Safety as assessed by the incidence, seriousness, and severity of 
adverse events (AEs). 
• 
Time to disease control by treatment day/week. 
• 
Time to rescue therapy by treatment day/week. 
• 
Change from baseline in BPDAI score by treatment week and at 
disease control. 
• 
Change from baseline in pruritus as evaluated by the BPDAI-VAS 
by treatment week and at disease control. 
• 
Change from baseline in skin biopsy 
 at disease 
control. 
• 
Evaluation of total cumulative steroid exposure at baseline, by 
treatment week and at disease control. 
• 
Evaluation of maximum daily steroid dose at baseline, by treatment 
week and at disease control. 
 
Exploratory Endpoints: 
• 
Change from baseline in blister fluid protein levels 
 
at treatment Week 1. 
• 
Change from baseline in blood
 levels by treatment week 
and at disease control. 
• 
Change from baseline in Anti-BP180 IgG levels by treatment week 
and at disease control. 
• 
Evaluations of complete blood count (CBC), blood chemistry, and 
serum protein levels 
 
at baseline, by treatment week and at disease control. 
• 
Changes in AKST4290 plasma concentrations at various timepoints. 
• 
Change from baseline in cognitive assessments using the MoCA at 
disease control. 
• 
Change from baseline in quality of life, as assessed by the DLQI at 
disease control. 
• 
Evaluation of exploratory biomarkers in plasma samples at various 
timepoints. 
 
Population: 
Approximately 30 subjects, between 60 to 95 years of age (inclusive), with a 
baseline diagnosis of mild to moderate BP. 

 
 
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The overall duration of the study is approximately 15 months from study initiation (i.e., first subject enrolled) to 
study completion (i.e., last subject last visit) with a targeted recruitment of 30 subjects over the accrual period. 
The planned duration of subject participation is approximately 5 weeks, which includes 1 to 3 weeks of inpatient 
treatment to achieve disease control followed by a 14-day [2 weeks] outpatient period to the Safety Follow-up 
call, or until withdrawal from the study for any reason. 
 
4.2 
STUDY ENDPOINTS 
 
4.2.1 
PRIMARY ENDPOINT 
 
Primary Endpoint: 
• The proportion of subjects who achieve disease control (≤ 3 new blisters/day and healing of existing 
blisters) without requiring rescue therapy. 
 
4.2.2 
SECONDARY ENDPOINTS 
 
Secondary Endpoints: 
• 
Safety as assessed by the incidence, seriousness, and severity of AEs. 
• 
Time to disease control by treatment day/week. 
• 
Time to rescue therapy by treatment day/week. 
• 
Change from baseline in BPDAI score by treatment week and at disease control. 
• 
Change from baseline in pruritus as evaluated by the BPDAI-VAS by treatment week and at disease 
control. 
• 
Change from baseline in skin biopsy 
 levels at disease control. 
• 
Evaluation of total cumulative steroid exposure at baseline, by treatment week and at disease control. 
• 
Evaluation of maximum daily steroid dose at baseline, by treatment week and at disease control. 
4.2.3 
EXPLORATORY ENDPOINTS 
 
Exploratory Endpoints: 
• 
Change from baseline in blister fluid protein levels 
 at treatment Week 1. 
• 
Change from baseline in blood 
 levels by treatment week and at disease control. 
• 
Change from baseline in Anti-BP180 IgG serum levels by treatment week and at disease control. 
• 
Evaluations of complete blood count [CBC], blood chemistry, and serum protein levels 
 
 at baseline, by study week and at disease control. 
• 
Changes in AKST4290 plasma concentrations at various timepoints. 
• 
Change from baseline in cognitive assessments using the MoCA at disease control. 
• 
Change from baseline in quality of life, as assessed by the Dermatology Life Quality Index (DLQI) 
at disease control. 
• 
Evaluation of exploratory biomarkers in plasma samples at various timepoint. 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible for inclusion, all subjects must meet the following criteria: 
1. Age 60-95 years, inclusive at screening. 

 
 
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Modification of Diet in Renal Disease (MDRD) study equation (see Section 17.5). 
13. Use of systemic steroids (>10 mg prednisone or equivalent/day) within 14 days of first dose of study 
agent or known diseases (other than BP) that could require the use of systemic steroids within the study 
period. Subjects who have received a single high-dose of steroids (intravenous or oral) 14 days or more 
before the administration of the first dose of study drug are eligible for enrollment. 
14. Clinically relevant abnormal laboratory value at screening, including hematology, blood chemistry, or 
urinalysis (laboratory testing may be repeated once during the screening phase). 
15. Significant alcohol or drug abuse within past 2 years. 
16. Based on ECG reading, subjects with a risk of QT prolongation including: 
• 
A baseline prolongation of QTc (using Fridericia’s formula: ≥ 450 ms in men and ≥ 470 ms in 
women) with confirmation on a repeat ECG. 
• 
A history of additional risk factors for Torsades de pointes arrhythmia (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome, etc.). 
17. The use of concomitant medications known to prolong the QT/QTc interval. 
18. Significant medical conditions (as determined by medical history, examination, and clinical investigations 
at screening) that may, in the opinion of the investigator, result in the any of the following: 
• 
Put the subject at risk because of participation in the study. 
• 
Influence the results of the study. 
• 
Cause concern regarding the subject’s ability to participate in the study. 
19. Malignancy for which the subject is currently undergoing resection, radiation, or chemotherapy. 
20. Participation in studies of investigational drugs must have been discontinued within 30 days or 
5 half-lives of the drug (whichever was longer) prior to screening. 
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
The Sponsor does not anticipate any specific challenges in meeting recruitment goals of enrolling and retaining a 
total of 30 subjects in this study. Subjects will be recruited continuously until the planned sample size is achieved. 
Subjects who withdraw or are withdrawn during screening, as well as subjects who discontinue, may be replaced 
(see Section 5.4.2 ). 
 
The expected length of participation in the study of approximately 5 weeks, which includes 1 to 3 weeks of 
inpatient treatment to achieve disease control followed by a 14-day [2 weeks] outpatient period to the Safety 
Follow-up call, is not expected to be challenging to subjects. Financial support for meal and miscellaneous 
expenses will be available during the study, as appropriate and based on local regulations and guidelines. The 
study will be entered into local clinical trial registries, as required. 
 
5.4 
SUBJECT WITHDRAWAL  
 
5.4.1 
REASONS FOR WITHDRAWAL 
 
 
A subject may be withdrawn from the study for the following medical or administrative reasons: 
• 
Occurrence of an AE that represents an unacceptable risk to the subject and when continued participation 
in the investigational study is not warranted, in the judgment of the investigator, Sponsor, or medical 
monitor. The investigator must follow the subject until the AE resolves or is stable, unless the subject is 
lost to follow up. 
• 
Treatment with a prohibited concomitant medication other than the use of appropriate medications for the 
treatment of AEs under direction of the investigator. 

 
 
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• 
Subject noncompliance, defined as refusal or inability to adhere to the trial schedule or procedures. 
• 
At the request of the subject (e.g., subject withdraws consent), investigator, Sponsor, or regulatory 
authority. 
• 
Pregnancy. 
• 
Subject did not achieve disease control (as defined per protocol) following 3 weeks of treatment with 
study agent (please see Schematic of Study Design for more information). 
 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS 
 
Subjects will be encouraged to complete the study and all assessments. Subjects may voluntarily withdraw at 
any time, and the investigator may discontinue individual subjects from the study at any time. 
 
Approximately 30 subjects will be enrolled in the study with the intent of obtaining 27 evaluable subjects, 
assuming a 10% dropout rate. Subjects who discontinue or are unblinded prior to treatment Week 1 may be 
replaced. Subjects who withdraw or are withdrawn during screening will be replaced. 
 
Subjects who have received at least 1 dose (400 mg) but are withdrawn or withdraw from the study will be 
encouraged to complete the EOT visit procedures and the Safety Follow-up call. The primary reason for study 
discontinuation will be documented on the case report form (CRF). 
 
Subjects that are withdrawn at the end of Week 3 of treatment due to lack of disease control will perform all 
EOT visit procedures and the Safety Follow-up call. The primary reason for withdrawal will be documented 
on the CRF. 
 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
 
The Sponsor reserves the right to terminate the study at any time. Should this be necessary, the Sponsor and/or 
their representatives will arrange discontinuation procedures and notify the appropriate regulatory authority(ies), 
IRBs, and IECs. In terminating the study, the Sponsor and the investigator will continue to protect the subjects’ 
privacy and identity as required by relevant statues and regulations. 
 
Alkahest, Inc. has the right to terminate a study site from participating in the study at any time. Reasons for study 
or site termination may include, but are not limited to: 
• 
(Immediate) risk to subject safety. 
• 
Unsatisfactory subject enrollment. 
• 
Unacceptable protocol deviations/violations as assessed by the medical monitor. 
• 
Inaccurate or incomplete data entry and recording/fabricated data. 
• 
Investigational site noncompliance with ICH GCP. 
• 
Unacceptable emergent safety profile. 
 
6 
STUDY AGENTS 
6.1 
STUDY AGENT AND CONTROL DESCRIPTION 
 
6.1.1 
ACQUISITION 
 
The study agent (AKST4290) and placebo will be manufactured, labeled, packaged, and distributed by 
Alkahest, Inc. The co-administered agent, MFC, will be supplied by the study sites. Likewise, if rescue 

 
 
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therapy is required, including CPC and/or oral prednisone, study sites will supply these treatments. At the 
conclusion of the study, sites may be reimbursed by Alkahest for MFC, CPC, and oral prednisone 
administered to subjects during the course of the study (see Section 6.2), as applicable. 
 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
AKST4290 is a film-coated pink, oblong tablet manufactured by Alkahest, Inc., with a unit strength of 
400 mg. The study agent and matching placebo will be delivered to the site, and the drug products will be 
labeled for investigational use only according to applicable local regulatory requirements for clinical studies. 
 
For further details and information on AKST4290 and placebo, including packaging and labeling, see the 
Investigator’s Brochure.  
 
6.1.3 
PRODUCT STORAGE AND STABILITY 
 
The study agent and placebo will be kept in its original packaging in a secure limited access storage area at 
15° C - 30° C. A temperature log must be maintained to make certain the study agent and placebo are stored 
at the correct temperature. If the storage conditions are found to be outside the specified range, the site must 
immediately notify the sponsor or designee. 
 
Co-administered steroids and rescue treatments should be stored according the product labels and study 
site/institutional policies. 
 
6.1.4 
DOSING AND ADMINISTRATION 
 
The study agent or placebo will be administered orally twice daily (b.i.d.).During the course of the study, all 
study agent and placebo administration will be performed at the study site under the direct supervision of the 
study personnel for documentation of precise administration times. 
 
During the study, topical whole-body MFC will be co-administered. The baseline dose will be dependent 
upon disease severity as assessed by the investigator and will remain unchanged until disease control or until 
rescue is indicated, per protocol guidelines. The guidelines for baseline dose of MFC is once a day application 
for mild BP subjects and b.i.d. application for moderate BP subjects, per investigator discretion.  
 
Subjects requiring rescue therapy will receive whole-body CPC, 15-50 g per day (dose and frequency per 
investigator discretion) and/or oral prednisone (0.5 mg/kg per day), as determined by the investigator if their 
condition worsens at any time during the study or fails to improve after Week 1 on treatment. 
 
6.2 
STUDY AGENT ACCOUNTABILITY 
 
The investigator and/or pharmacist will receive the study agent/placebo delivered by the sponsor when the 
following requirements are fulfilled: 
• 
Approval of the clinical study protocol and Informed Consent by the IRB or IEC 
• 
Availability of a signed and dated clinical trial contract between the sponsor and the investigational site 
• 
Approval/notification of the appropriate regulatory authority 
• 
Availability of the curriculum vitae of the principal investigator 
• 
Availability of a signed and dated clinical study protocol by principal investigator 
 

 
 
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The investigator and/or pharmacist must maintain records of the study agent/placebo delivery to the study site, the 
inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused 
study agent/placebo. In addition, for purposes of reimbursement of co-administered agents and rescue treatments, 
the investigator and/or pharmacist must maintain records of the use by each subject. At the conclusion of the study, 
reimbursement for co-administered agents and rescue treatments will be distributed on the basis of these records. 
 
For the study agent/placebo, records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, 
and the unique code numbers assigned to the study agent/placebo and subjects. The investigator/pharmacist will 
maintain records that document adequately that the subjects were provided the doses specified by the protocol and 
reconcile all study agent/placebo received from the sponsor. At the time of final study agent/placebo reconciliation, 
the investigator/pharmacist must verify that all unused or partially used portions of study agent/placebo have been 
returned and that no remaining study agent/placebo is retained by the investigator. 
 
Accountability records must be maintained and readily available for inspection/audits by representatives of 
Alkahest, Inc. or their designee and are open to inspections by regulatory authorities at any time. The accounts of 
any study agent/placebo accidentally wasted or intentionally disposed of must be maintained. 
 
The disposal of used, partially used, or wasted study agent/placebo materials must be performed in accordance 
with the institution’s drug disposal policy. At study initiation, the clinical study monitor will evaluate the site’s 
standard operating procedure for study drug disposal/destruction to ensure it complies with study requirements. At 
the end of the study, following final study agent/placebo reconciliation by the monitor, the study site will be 
instructed by the sponsor to return or destroy all unused study agent/placebo supplies, including empty containers. 
In case of destruction according to the site’s drug disposal/destruction policy, a certificate of destruction must be 
issued and provided to the Sponsor. A copy of the institution’s drug disposal policy and certificate of destruction, if 
applicable, should be maintained or referenced in the Investigator Site File (ISF). 
 
7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
 
7.1.1 
STUDY SPECIFIC PROCEDURES 
 
7.1.1.1 Screening Procedures 
Subjects must be admitted to the hospital/site or in the process of being admitted at the time of screening. 
During screening, the following will be performed: 
• 
Assessment of BP including the following: 
o BPDAI 
o BPDAI-VAS 
• 
Medical history 
• 
Demographics 
• 
Review of medications, including steroids 
• 
Vital signs 
• 
Physical examination 
• 
12-Lead ECG 
• 
Blood and urine collection for laboratory evaluations 
• 
Skin biopsy for confirmation of BP by immunohistochemistry (IHC) (note: histological confirmation of 
BP is not required for initial eligibility) 
 

 
 
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Detailed descriptions of each of these procedures are provided in the sections immediately following. 
Information pertaining to all study activities performed during screening, and the sequence of events, is 
provided in Section 7.3.1. 
 
7.1.1.1.1 Assessment of Bullous Pemphigoid/Steroid Dose Determination 
At screening and baseline, subjects will be assessed for clinical diagnosis of BP and severity of disease will 
be assessed. Only subjects with mild (BPDAI ≤ 10 OR < 10% affected body surface) or moderate (BPDAI > 
10 and < 55 OR 10%-30% affected body surface) disease are eligible for participation. Investigators will also 
obtain skin biopsy and draw blood samples to test for antibodies for subsequent histologic confirmation of BP 
per the S2k Guideline for the Diagnosis of Pemphigus Vulgaris/Foliaceus and Bullous Pemphigoid 
(Schmidt 2015). Histological confirmation of BP is not required prior to randomization, but is required prior 
to participation in follow-on open-label, 12-month treatment study. 
 
 
The investigator will also select the initial dose and frequency of topical MFC, per disease severity and 
investigator assessment. The guidance for initial frequency of MFC application at baseline is once per day 
application for mild BP subjects, and twice daily (b.i.d.) application for moderate BP subjects. The dose and 
frequency selected at baseline will be the same dose used throughout the study, unless rescue therapy is 
required. Initial whole-body topical steroid therapy (clobetasol propionate class) prior to study entry is 
allowed for up to and including 7 days prior to enrollment. Additionally, subjects who have received a single 
high-dose of steroids (intravenous or oral) 14 days or more before the administration of the first dose of study 
drug are eligible for enrollment. There is no restriction for the number of days of prior lesion-only topical 
steroid treatment. Total prior steroid dose will be captured in the eCRFs. 
 
7.1.1.1.2 Medical History 
The investigator or designee will obtain a detailed medical history through interview with the subject during 
screening. The medical history should focus on recent history, with an emphasis on the history of symptoms 
related to BP. Additionally, the medical history should include: 
• 
Current/past illnesses and conditions 
• 
Current symptoms of any active medical condition 
• 
Surgeries and procedures 
• 
Allergies 
• 
Social history (e.g., exercise, smoking, alcohol, illegal substances) and current living situation 
• 
Cause of parental death (if not living) 
 
7.1.1.1.3 Demographics 
Demographic information such as the subject’s education level, ethnicity, and race will be collected by 
interview with the subject at screening. 
 
7.1.1.1.4 Review of Medications 
The investigator or designee should obtain a complete list of the subject’s current medications, including 
over-the-counter drugs, herbal supplements and/or vitamins, as well as those taken by the subject in the past 
12 months. Assessment of eligibility should include a review of permitted and prohibited medications. Any 
additions, discontinuation, or dosage changes in medication during the course of the study will be recorded. 
 
7.1.1.1.5 Vital Signs 
Vital signs will include seated systolic and diastolic blood pressure (mm Hg), heart rate (beats per minute 
[bpm]), respiration rate (breaths per minute), and body temperature. Vital signs will be measured after the 
subject has been seated for 5 minutes. 

 
 
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7.1.1.1.6 Physical Examination 
A full physical examination will be performed to assess the following organ systems: skin, ENT (ears, nose, 
and throat), head, eyes, lungs/chest, heart, abdomen, musculoskeletal, extremities, neurologic and lymphatic 
systems. Height will be measured at screening and weight will be monitored during the trial. 
 
7.1.1.1.7 12-Lead ECG 
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a computerized 
electrocardiograph. A 12-lead ECG will be performed after the subject has rested quietly for at least 5 minutes 
in a supine position. In some cases, it may be appropriate to repeat abnormal ECGs to rule out technical 
factors contributing to ECG artifacts or abnormality. It is important that leads are placed in the same positions 
each time for consistency. The overall conclusion with the interpretation of the ECGs will be recorded on the 
appropriate CRF. The interpretation of the ECGs will be recorded as normal, abnormal but not clinically 
significant, or abnormal and clinically significant. QTc intervals will be calculated using Fridericia’s 
correction formula and entered into the CRF. 
 
7.1.1.1.8 Screening Biological Specimen Collection 
For screening evaluation, blood will be drawn by a qualified medical provider, and urine specimens will also 
be collected (also see Section 7.1.1.2.6 and Schedule of Events). 
 
7.1.1.1.9 Skin Biopsy 
For disease confirmation, a skin biopsy will be obtained for IHC. Instructions on biopsy sampling and 
processing through a separate Laboratory Manual. 
 
7.1.1.2 Procedures to Assess Safety 
Subjects enrolled in the trial will be monitored closely to assess safety and tolerability of the study agent and 
intervention. Study specific procedures that will be used for this purpose are summarized below. Information 
regarding the timing and frequency of these procedures is provided in Section 7.3. 
• 
Review of AEs 
• 
Review of medications 
• 
Review of daily SOC disease assessments  
• 
Vital signs 
• 
Targeted physical examinations and weight 
• 
EOT (or Withdrawal) physical examination 
• 
Blood and urine collection for laboratory evaluations 
 
7.1.1.2.1 Review of Adverse Events 
AEs will be reviewed, documented, and reported as required at each visit, beginning at screening. For 
definitions, guidance, and additional information regarding AEs, refer to Section 8. 
 
7.1.1.2.2 Review of Medications 
The investigator or designee should review the subject’s current medications, including over-the-counter 
drugs, herbal supplements and/or vitamins, as well as those taken by the subject since the last visit. Changes 
to the subject’s list of medications should be reviewed and recorded. Review of medications should occur at 
every visit. 
 

 
 
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7.1.1.2.3 Review of Daily Standard of Care Disease Assessments 
Per SOC, disease assessment will be performed on a daily basis to assess safety and disease control. At each 
schedule study visit, SOC disease assessments will be reviewed and documented in the CRF per the Schedule 
of Events. If disease control is indicated at any point during the study, the EOT visit should be performed and 
the date of disease control will be recorded in the CRF.  
 
7.1.1.2.4 Vital Signs 
Refer to Section 7.1.1.1.5 for a description of vital signs and weight measurements. Vital signs will be 
collected at every visit (see the Schedule of Events). 
 
7.1.1.2.5 Targeted Physical Examination 
During the study period, a targeted physical examination, including auscultation of the heart and body weight, 
will be performed per the Schedule of Events. 
 
7.1.1.2.6 Blood and Urine Collection for Laboratory Evaluations 
Blood samples and urine will be collected according to the Schedule of Events. All safety laboratory 
measurements will be performed by a Clinical Laboratory Improvement Amendments-certified laboratory. 
Investigators will receive guidance and instructions on laboratory sampling and processing through a separate 
Laboratory Manual provided by the central laboratory. 
 
Laboratory tests collected will include the following per the Schedule of Events: 
• 
Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
, platelets 
• 
Chemistry: glucose, sodium, potassium, calcium, inorganic phosphate, chloride, bicarbonate, 
magnesium, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), lactate dehydrogenase, direct and indirect bilirubin, blood urea nitrogen, total 
protein, albumin 
• 
Serology: HBV, HCV, HIV, and QuantiFERON testing for TB. 
• 
Coagulation: activated partial thromboplastin time, prothrombin time/international normalized ratio 
(INR) 
• 
Urinalysis: pH, glucose, erythrocytes, leukocytes, protein, nitrite 
• 
Serum Proteins (exploratory): 
 
• 
Blister fluid proteins: ECP, IL-5, IL-6 (only at screening and Week 1) 
• 
Anti-BP180 Antibodies: Anti-BP180 IgG serum levels 
• 
Pregnancy test in WOCBP (only at screening and EOT) 
 
Additional laboratory parameters may be reported, as detailed in the laboratory manual. Glomerular filtration 
rate (GFR) will be estimated by the MDRD formula utilizing serum creatinine (see Section 17.5).  
 
Serology will only be conducted at screening. Potential subjects with positive screening test result for HBV, 
HCV, or HIV will not be eligible for study participation. Any subjects with active signs of TB will be 
excluded from the study. All subjects will be tested for TB at screening. Subjects meeting all other eligibility 
requirements will be randomized for study participation while awaiting TB tests results (QuantiFERON) 
which may require several days for processing. If the TB test results are positive, the subject will be 
discontinued from the study.  
 
The investigator is responsible for determining and documenting if out of range laboratory values are 
clinically significant. All clinically significant values will be recorded as AEs in the eCRF and followed until 

 
 
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resolution. Once resolved, the appropriate eCRF page(s) will be updated. 
 
Samples may be used for re-testing, further evaluation of an AE and/or assessment, and follow up of other 
exploratory endpoints. Samples that remain after study testing is complete will be stored in the event 
additional testing (e.g., further evaluation of an AE or assessment of effect) is required. Samples will be 
stored in a deidentified coded form. Subjects can opt out of storage of samples for future analysis. 
 
7.1.1.3 Procedures to Assess Efficacy 
The assessment of disease control (≤ 3 new blisters/day and healing of existing blisters) following topical 
steroid treatment with adjunctive AKST4290 will be performed. During the treatment period, daily SOC 
assessments of disease will be performed between scheduled study visits and will be reviewed by the site staff 
and recorded in the study source documentation and in the clinical study database, as available. Time to 
disease control will be assessed and compared across treatment groups. Change in BPDAI score will be 
assessed following treatment until disease control. Change in pruritus as evaluated by the BPDAI-VAS will 
be assessed until disease control. The steroid regimen and total dose used during the study period will be 
evaluated. Change in skin biopsy 
 levels and change in blister fluid protein levels will also be 
evaluated. Change in cognition (as assessed by MoCA) and change in quality of life (as a by DLQI) will be 
evaluated. 
 
Descriptions of each assessment are provided below. 
 
7.1.1.3.1 Bullous Pemphigoid Disease Area Index Tool 
The BPDAI tool (Murrell 2012) computes 2 scores: total BPDAI activity and total BPDAI damage. The total 
BPDAI activity score is the arithmetic sum of the 3 subcomponents – cutaneous blisters/erosions, cutaneous 
urticaria/erythema, and mucosal blisters/erosions. The total BPDAI damage score is the arithmetic sum of the 
items rated regionally for damage caused by more permanent features such as post-inflammatory 
hyperpigmentation, scarring, and other. The BPDAI quantifies lesion number and size thresholds, and lesions 
are rated based on the regions affected. Additional weighting is given to areas of the skin primarily affected in 
BP, such as the limbs, and less emphasis to scalp and face, to better differentiate clinical response in BP. 
Scores can range from 0 to 360 for BPDAI total activity (maximum 240 for total skin activity and 120 for 
mucosal activity), and 0 to 12 for BPDAI damage, with higher scores indicating greater disease activity or 
damage. An example of the BPDAI tool is provided in Section 17.1. 
 
7.1.1.3.2 Bullous Pemphigoid Disease Area Index Tool Visual Analog Scale (BPDAI-VAS) 
Pruritus, a major symptom of the onset or recurrence of BP, is measured using a separate subjective 
component of the BPDAI (Murrell 2012). The intensity of pruritus is assessed using a visual analog scale to 
answer the question, ‘‘How severe is your itching today?’’ and the subject marks an ‘‘x’’ on the 0- to 10-cm 
line where 0 is no itch and 10 is maximal itching. The degree of itching is measured as the distance in 
centimeters from 0, out of 10. This is repeated for the severity overall of itching in the past week and month. 
A total score is calculated from this out of 30. An example of the BPDAI-VAS is provided in Section 17.2. 
 
7.1.1.3.3  Dermatology Life Quality Index 
The DLQI is a 10 question tool designed to assess the impact of skin diseases on a subject’s quality of life 
(Finley 1994). The questionnaire was structured with each question having 4 alternative responses: 'not at all', 
'a little', 'a lot' or 'very much' with corresponding scores of 0, 1, 2 and 3, respectively. The answer 'not 
relevant', is scored as '0'. The DLQI is calculated by summing the score of each question, resulting in a 
maximum of 30 and minimum of 0. The higher the score, the greater the impairment of quality of life. The 
DLQI can also be expressed as a percentage of the maximum possible score of 30. An example of the DLQI is 
provided in Section 17.3. 

 
 
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7.1.1.3.4 Skin Biopsy and Blister Fluid Assessments 
A skin biopsy will be required to confirm the histological diagnosis of BP by IHC and to assess skin 
 levels. Skin biopsies will be collected at screening and will be requested at disease control 
(optional). Skin biopsies will be performed only if blisters are present and at the margin of the blister. 
 
Blister fluid protein levels 
 will be assessed at baseline and Week 1. Blister fluid will be 
collected directly from the blisters that have not been drained and/or ruptured by using a sterile hypodermic 
needle and syringe. The blister fluid will be aliquoted and stored frozen at the site until shipped to the lab. 
Blister fluid assessment will not be performed if there is no detectable fluid or active blister present at time of 
scheduled assessment. 
 
7.1.1.3.5 Montreal Cognitive Assessment 
The MoCA has been designed as a rapid screening instrument to detect mild cognitive impairment (MCI) 
(Nasreddine 2005). It is a commonly used screening test easily administered by nonspecialist staff. It assesses 
the domains of attention and concentration, executive functions, memory, language, visuoconstructional 
skills, conceptual thinking, calculations, and orientation. The total possible score is 30 points with a score of 
26 or more considered normal. Time to administer the MoCA is approximately 15 minutes. The total possible 
score is 30 points. An example of this tool is provided in Section 17.4. 
 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 
CLINICAL LABORATORY EVALUATIONS 
 
Biological samples (e.g. whole blood, serum, plasma, urine) will be collected for laboratory evaluations in 
accordance with the Schedule of Events. Refer to the study’s Laboratory Manual for complete information 
regarding all laboratory evaluations to be performed, sample collection procedures, and related requirements. 
 
The investigator is responsible for determining and documenting whether out of range laboratory values are 
clinically significant. All clinically significant values will be recorded as AEs in the CRF and followed until 
determined to be stable or resolved, unless the subject is lost to follow up. Once resolved, the appropriate 
CRF page(s) will be updated. 
 
7.2.2 
OTHER TESTS OR PROCEDURES 
 
7.2.2.1  
Study Agent Concentration and Pharmacokinetics 
Plasma concentration measurements of AKST4290 and its major metabolites will be assessed to determine 
systemic exposure to the study agent. For required and optional sampling time points and further details, 
please refer to Section 17.8.1. 
 
7.2.2.1.1  Pharmacokinetic Endpoints 
As far as feasible, the following PK parameter will be summarized descriptively:  
• 
Cpre,ss,N 
Pre-dose concentration of AKST4290 in plasma immediately before administration of 
the Nth dose 
 
7.2.2.1.2  Methods of Sample Collections 
Details regarding collection, sample handling, and shipment instructions will be provided in the Laboratory 
Manual. 

 
 
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7.2.2.1.3  Analytical Determinations 
Concentrations of AKST4290 and metabolites (if feasible) in plasma samples will be determined by a 
validated high-performance liquid chromatography, tandem mass spectrometry assay. Leftover samples will 
be used for exploratory biomarker assessment (see Section 7.2.2.2). 
 
7.2.2.2  
Plasma Biomarkers 
Measurement of biomarkers is exploratory. Investigations might include mechanism related markers 
 which could identify subsets of 
subjects who may benefit most from the treatment with AKST4290. Other disease related markers may 
include inflammatory mediators or markers of oxidative stress. Biomarkers will be measured in plasma 
samples to investigate any change in response to treatment. After completion of the study, leftover samples 
may be used for further methodological and/or other, non-genetic biomarker investigations either by the 
Sponsor, or designee. The study samples will be discarded after completion of the additional investigations, 
but not later than 3 years after the final study report has been archived. The exploratory biomarker 
measurements will be conducted either at the Sponsor’s labs or at external Contract Research Organizations 
(CROs) using appropriate methodology (e.g., immunoassays, multiplex technology). Details regarding 
collection, sample handling, and shipment instructions will be provided in the Laboratory Manual. 
 
7.2.2.3 
Serum Protein Evaluation 
Evaluation of serum proteins is exploratory. Details regarding collection, sample handling, and shipment 
instructions will be provided in the Laboratory Manual. 
 
 
7.3 
STUDY SCHEDULE 
 
7.3.1 
SCREENING 
 
7.3.1.1 Visit 1, Screening Visit (Day -3 to 0) 
The following procedures will be performed during the Screening Visit, as per the Schedule of Events: 
 
• 
Signing of all applicable informed consents must be completed prior to any study-related assessments 
• 
Verify clinical diagnosis of BP and perform specified assessments: 
o BPDAI (see Section 7.1.1.3.1) 
o BPDAI-VAS (see Section 7.1.1.3.2) 
o Skin biopsy (see Section 7.1.1.3.4) 
• 
Obtain medical history, including medical records and test results to support BP diagnosis, if available 
• 
Collect demographic information 
• 
Review subject’s current and prior medications 
• 
Review prohibited medications and substances with the subject 
• 
Collect vital signs 
• 
Collect clinical laboratory tests (see Section 7.1.1.2.6) 
o Hematology 
o Chemistry 
o Serology 
o Coagulation 
o Urinalysis 
o Serum Proteins 

 
 
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o Anti-BP180 antibodies 
o Pregnancy test in WOCBP 
• 
Perform full physical examination (including height) 
• 
Perform 12-lead ECG 
• 
Verify the subject fulfills all the inclusion criteria and none of the exclusion criteria 
• 
AE reporting and evaluation 
 
7.3.2 
BASELINE 
 
7.3.2.1 Visit 2, Baseline (Day 1) 
 
To be enrolled, the subjects must be inpatient and remain inpatient until disease control/EOT. All baseline 
procedures will be performed following admission, unless already admitted. 
• 
Following confirmation of eligibility, subject will be randomized to AKST4290 or placebo 
• 
Perform Specified assessments: 
o BPDAI (see Section 7.1.1.3.1) 
o BPDAI-VAS (see Section 7.1.1.3.2) 
o DLQI (see Section 7.1.1.3.3) 
o MoCA (see Section 7.1.1.3.5) 
o Topical steroid MFC dose and frequency assignment 
• 
Review concomitant medications 
• 
AE reporting and evaluation 
• 
Perform targeted physical examination 
• 
Collect vital signs 
• 
Collect clinical laboratory tests (see Section 7.1.1.2.6) 
o Hematology 
o Chemistry 
o Coagulation 
o Urinalysis 
o Serum Proteins 
o Anti-BP180 antibodies 
o Blister fluid 
• 
PK (required and optional) samples and biomarker samples (see Section 7.2.2.1 and Section 7.2.2.2)  
• 
Study agent and topical steroid dispensing/administration 
• 
Study agent accountability 
 
7.3.3 
TREATMENT 
 
The examinations of each visit are specified in Section 15. In addition, please see Section 17.8 for detailed 
information regarding PK evaluations. Weekly study visits will be performed up until the time of disease 
control/EOT. Important note: To ensure accuracy of PK sampling, study drug (AKST4290/placebo) should be 
administered during the study visit to enable appropriate timing of PK sample acquisition. 
 
7.3.3.1 
Visit 3/Week 1 (Day 7 ± 2) 
 
• 
Collect PK samples (see Section 7.2.2.1) (pre-dose) 
• 
Perform specified assessments: 
o BPDAI (see Section 7.1.1.3.1) 

 
 
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o BPDAI-VAS (see Section 7.1.1.3.2) 
o Assessment of disease control (see Section 7.1.1.3) 
o Assessment of need for rescue therapy 
• 
Perform targeted physical examination 
• 
Collect vital signs 
• 
Collect clinical laboratory tests (see Section 7.1.1.2.6) 
o Hematology 
o Chemistry 
o Coagulation 
o Urinalysis 
o Serum Proteins 
o Anti-BP180 antibodies 
o Blister fluid 
• 
Review concomitant medications 
• 
AE reporting and evaluation 
• 
Study agent and topical steroid dispensing/administration 
• 
Study agent accountability 
• 
Review and document daily SOC disease assessments performed since the previous study visit, as 
available 
 
7.3.3.2 
Visit 4/Week 2 (Day 14 ± 2)  
The following assessments will be performed at  study Week 2, and until disease control, regardless of rescue 
therapy administration. 
 
• 
Collect PK samples (see Section 7.2.2.1) (pre-dose) 
• 
Perform specified assessments: 
o BPDAI (see Section 7.1.1.3.1) 
o BPDAI-VAS (see Section 7.1.1.3.2) 
o Assessment of disease control (see Section 7.1.1.3) 
o Assessment of need for rescue therapy 
• 
Perform targeted physical examination 
• 
Collect vital signs 
• 
Collect clinical laboratory tests (see Section 7.1.1.2.6) 
o Hematology 
o Chemistry 
o Coagulation 
o Urinalysis 
o Serum Proteins 
o Anti-BP180 antibodies 
• 
Review concomitant medications 
• 
AE reporting and evaluation 
• 
Study agent and topical steroid dispensing/administration 
• 
Study agent accountability 
• 
Review and document daily SOC disease assessments performed since the previous study visit, as 
available 
 
7.3.3.3 
Unscheduled Visits 
Unscheduled visits may be conducted in between scheduled study visits for assessment of AEs, concomitant 

 
 
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medications, or disease control, but must not take the place of a scheduled weekly visit or EOT visit. 
 
• 
Review concomitant medications 
• 
AE reporting and evaluation 
• 
Assessment of disease control (see Section 7.1.1.3) 
• 
Assessment of need for rescue therapy 
• 
Topical steroid assessment 
• 
Study agent and topical steroid dispensing/administration 
• 
Study agent accountability 
 
7.3.3.4 
End of Treatment Visit/Visit 5/Week 3 (Day 21 ± 2) 
The EOT visit should be conducted at any time during the study once the subject has achieved disease 
control, as assessed by the investigator or at the time of withdrawal (see Section 5.4.1). This visit can be 
performed outside the weekly visit and in place of the next scheduled visit. If a previously completed weekly 
visit was performed within 2 days of the EOT visit, then only the procedures unique to the EOT visit must be 
performed. 
 
Subjects that do not reach disease control by treatment Visit 5/Week 3 (Day 21 ± 2) (see Section 5.4.1) will 
be discontinued and required to perform all EOT procedures. 
 
• 
Collect PK and biomarker samples (see Section 17.8.1)  
• 
Perform specified assessments: 
o BPDAI (see Section 7.1.1.3.1) 
o BPDAI-VAS (see Section 7.1.1.3.2) 
o DLQI (see Section 7.1.1.3.3) 
o Assessment of disease control (see Section 7.1.1.3) 
o Skin biopsy (optional) (see Section 7.1.1.3.4) 
o MoCA (see Section 7.1.1.3.5) 
• 
Collect clinical laboratory tests (see Section 7.1.1.2.6) 
o Hematology 
o Chemistry 
o Coagulation 
o Urinalysis 
o Serum Proteins 
o Anti-BP180 antibodies 
o Pregnancy test in WOCBP 
• 
Perform full physical examination 
• 
Perform 12-lead ECG 
• 
Collect vital signs 
• 
Review concomitant medications 
• 
AE reporting and evaluation 
• 
Study agent and topical steroid dispensing/administration 
• 
Study agent accountability 
• 
Review and document daily SOC disease assessments performed since the previous study visit, as 
available 
• 
Documentation of confirmation of histological BP diagnosis per the S2k Guideline for the Diagnosis 
of Pemphigus Vulgaris/Foliaceus and Bullous Pemphigoid (Schmidt 2015) for potential participation 
in the follow-on open-label, 12-month treatment study 

 
 
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• 
Laboratory test abnormalities, if they represent a clinically significant finding, symptomatic or not, which 
were not present at baseline or worsened during the course of the study. 
 
An AE DOES NOT include a/an: 
• 
Elective medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion). 
• 
Pre-existing diseases or conditions present or detected at the start of the study that do not worsen. 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for cosmetic 
elective surgery, social and/or convenience admissions). 
• 
Overdose of either study drug or concurrent medication without any signs or symptoms. 
• 
Pregnancy. 
 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS 
 
Note: if either the investigator or the Sponsor believes that the event is serious, the event must be considered 
serious and evaluated for expedited reporting. 
 
Note: the terms “severe” and “serious” are not synonymous. Severity (or intensity) refers to the grade of an 
AE. “Serious” is a regulatory definition. 
An SAE (experience) or reaction is an untoward medical occurrence that, at any dose, fulfills one or more of 
the following criteria: 
 
a. Results in death (i.e., the AE actually causes or leads to death). 
b. Is life threatening. 
o An AE is considered “life threatening” if, in the view of either the investigator or Sponsor, its 
occurrence places the patient or subject at immediate risk of death; it does not include AEs which, 
had it occurred in a more severe form, might have caused death. 
c. Results in inpatient hospitalization or prolongation of existing hospitalization. 
o Hospitalization for elective treatment of a pre-existing condition that did not worsen during the 
study is not considered an AE; hospitalization for participating in this study is not considered an 
AE. 
o Complications that occur during hospitalization are AEs; if a complication prolongs 
hospitalization, the event is an SAE. 
o “Inpatient” hospitalization means the subject has been formally admitted to a hospital for medical 
reasons that may or may not be overnight; it does not include presentation at a casualty or 
emergency room unless the event meets the definition of an Important Medical Event (in the 
opinion of the investigator or Sponsor). 
d. Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
o The term ‘disability’ means a substantial disruption of a person’s ability to conduct normal life 
functions; this definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, accidental 
trauma (i.e., sprained ankle) that may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Results in a congenital anomaly in the offspring of a subject who received drug. 

 
 
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For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the 
Investigator’s Brochure listed only cerebral vascular accidents. "Unexpected" as used in this definition, also 
refers to AEs or suspected adverse reactions that are mentioned in the Investigator’s Brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug but are not specifically 
mentioned as occurring with the particular drug under investigation. For example, although angioedema is 
anticipated to occur in some patients exposed to drugs in the angiotensin-converting enzyme inhibitor class 
and angioedema would be described in the Investigator’s Brochure as a class effect, the first case of 
angioedema observed with the drug under investigation should be considered unexpected for reporting 
purposes. 
 
This definition of “unexpected” relies entirely on the Reference Safety Information in the Investigator’s 
Brochure as the basis for determining if newly acquired information generated from clinical trials or reported 
from other sources is unexpected. The suspected adverse reactions listed in the Investigator’s Brochure 
(i.e., “expected”) are those observed with the investigational drug and for which a causal relationship between 
the event and the drug is suspected or confirmed. 
 
Sponsor assessment of expectedness and relationship to study drug/causality will determine the need for 
expedited reporting of AEs. 
 
8.3 
TIME PERIOD/FREQUENCY FOR EVENT ASSESSMENT/FOLLOW-UP 
 
At every clinic visit, subjects who have given informed consent will be assessed for AEs and SAEs. After the 
subject has had an opportunity to spontaneously mention any problems, the investigator should inquire about AEs 
by asking a non-leading question such as the following: 
1. “How are you feeling?” 
2. “Have you had any changes since your last assessment/visit?” 
3. “Have you taken any new medicines since your last assessment/visit?” 
 
8.3.1 
POST-STUDY AE AND SAE 
 
The investigator is not obligated to actively seek SAE information in former study subjects, but the 
investigator is encouraged to notify Alkahest, Inc. or their designee of any AE or SAE occurring within 
30 days after a subject completes the study (or has their last visit) that the investigator judges may be 
reasonably related to study treatment or study participation. 
 
8.4 
REPORTING PROCEDURES 
 
8.4.1 
ADVERSE EVENT REPORTING 
 
All subjects who have given informed consent will be evaluated for AEs. All AEs that occur after the time of 
treatment with the study drug will be considered Treatment Emergent AEs. Subjects with Treatment 
Emergent AEs must be followed until the AE is resolved or is stable, unless the subject is lost to follow up. 
 
Each AE or suspected adverse reaction must be described as follows: the date of onset, date of resolution, 
severity (mild, moderate, severe), frequency of the event (single episode, intermittent, continuous), action 
taken with study treatment (no action taken, treatment held, treatment discontinued), outcome, causality* 

 
 
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(unrelated, possibly related, definitely related), and seriousness criteria. Each AE or suspected adverse 
reaction must be recorded separately. 
 
*Note: Causality assessment will be made only when the AE occurs after the subject has initiated at least 
1 dose of the study agent. An AE occurring before the subject’s exposure to study agent will always be 
labeled as “unrelated”. 
 
Any AE occurring during the study must be documented in the subject’s medical records and as an AE in the 
CRF. Any SAE occurring during the study must be documented in the subject’s medical records and as an 
SAE in the CRF. 
 
A separate set of SAE pages should be used for each SAE. However, if at the time of initial reporting, 
multiple SAEs are present that are temporally and/or clinically related, they may be reported on the same SAE 
page. 
 
The investigator should attempt to establish a diagnosis of the event (that meets the definition of an AE or 
SAE) based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs or symptoms. The diagnosis will become the 
basis for the verbatim term as reported by the investigator. If no diagnosis is known and clinical signs and 
symptoms are not present, the abnormal finding should be recorded. 
 
In addition to the investigator’s own description of the AE, each AE will be encoded according to the 
MedDRA. 
 
The investigator will take all appropriate and necessary therapeutic measures required for resolution of the 
AE. Any medication necessary for the treatment of an AE must be recorded on the concomitant medication 
CRF. 
 
The SAE pages of the CRF should be completed as thoroughly as possible and signed by the investigator or 
his/her designee before transmittal to the study CRO. It is very important that the investigator provide his/her 
assessment of causality to study drug as well as an applicable diagnosis at the time of the initial SAE report. 
 
8.4.2 SERIOUS ADVERSE EVENT REPORTING 
 
8.4.2.1 
Timeframes for Reporting Serious Adverse Events 
Under 21 CFR 312.32(c), the Sponsor is required to notify FDA, EMA, and all participating investigators in a 
safety report of potentially serious risks from clinical trials (i.e., Suspected Unexpected Serious Adverse 
Reactions [SUSARS]), as soon as possible after the Sponsor receives the safety information and determines 
that the information qualifies for reporting: 
• 
No later than 7 calendar days for events that are life threatening (in the opinion of the investigator or the 
Sponsor) or that involve Death as an outcome. 
• 
No later than 15 calendar days for all other SUSARS. 
 
As such, prompt notification of the Sponsor, and/or the Sponsor’s representatives, and promptly providing 
requested follow up information regarding SAEs is essential so that ethical and regulatory responsibilities and 
legal obligations can be satisfied. Investigators are responsible for reporting SAEs according to the following 
timeframes: 
 
• 
All SAEs occurring during the study should be reported immediately. 

 
 
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2. Halt dosing in all groups and stop the study. 
3. Continue with a modified protocol design and amend the protocol as appropriate. 
 
8.6 
SAFETY OVERSIGHT 
 
Safety oversight will be provided by the Sponsor’s Program Physician or his or her designee and the CRO’s 
Medical Monitor(s) in concert with the site investigators. There will be no formal Data Safety Monitoring Board 
established. As needed, Safety Evaluation Meetings will be convened as described in Section 8.5 to monitor the 
ongoing safety of the study. The Sponsor’s Program Physician or designee is the final authority for safety 
oversight in the study. 
 
9 
CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and wellbeing of human subjects are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). 
 
• 
Monitoring for this study will be performed by the study CRO in accordance with the Clinical Monitoring 
Plan (CMP). 
• 
A mix of onsite and centralized risk-based monitoring will be performed to ensure the safety of clinical 
subjects and the accuracy and completeness of study data. 
• 
The Sponsor will be provided with copies of monitoring reports per the timelines specified within the 
CMP. 
• 
Details of clinical site monitoring tasks and scope are documented in the study’s CMP. The CMP 
describes in detail who will conduct monitoring, at what frequency monitoring will be done, at what level 
of detail monitoring will be performed, and the distribution of monitoring reports. 
• 
Independent audits may be conducted by the Sponsor’s Quality Assurance (QA) function or Sponsor 
contracted QA consultants in accordance with a study specific QA Plan to ensure monitoring practices are 
performed consistently across all participating sites, that monitors are following the CMP and sites 
conduct the study according to the protocol, GCP, and applicable regulatory requirements. 
 
10 
STATISTICAL CONSIDERATIONS 
10.1 STATISTICAL DESIGN MODEL AND ANALYTICAL PLANS 
 
A Statistical Analysis Plan (SAP) with analytical details and assumptions will be developed and finalized before 
database lock and unblinding of the study data. 
 
10.2 STATISTICAL HYPOTHESES 
 
No formal hypothesis testing is planned for this study. Statistical comparisons will be made between placebo and 
AKST4290. 
 
10.3 ANALYSIS DATASETS 
 
Study data will be analyzed in one of the following analysis sets: 
• 
Intent-to-Treat (ITT) set will include all randomized subjects. 

 
 
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• 
Safety Evaluable set will include all randomized subjects who receive at least 1 dose of the study agent 
(placebo or AKST4290) 
• 
Per Protocol (PP) set is a subset of ITT subjects. A detailed description of the reasons for exclusion from 
the PP population will be included in the SAP. 
 
Subjects will be analyzed in the treatment arm assigned at randomization for the ITT and PP data sets. For the 
Safety Evaluable data set, subjects will be grouped according to actual treatment received. 
 
10.4 DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 
GENERAL APPROACH 
 
Subject disposition and protocol deviations will be summarized descriptively by treatment arm. The 
comparability between the treatment arms in demographics and baseline characteristics will be assessed. Prior 
and concomitant medications will also be summarized by treatment arm. 
 
All summary statistics will be descriptive unless noted otherwise. Descriptive summaries will include mean, 
standard deviation, median, and range for continuous variables and counts, and percentages for categorical 
variables. Two-sided 95% confidence intervals (CIs) will be provided for the means and percentages as 
needed. For key outcome measures, the difference between the treatment arm and the 95% CI of the 
difference will be computed. 
 
Detailed statistical methods will be outlined in the SAP for the study. 
 
10.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT 
 
The primary endpoint is the proportion of subjects who achieve disease control (≤ 3 new blisters/day and 
healing of existing blisters) without the use of rescue therapy. The proportion of subjects who achieve disease 
control will be compared between treatment groups on a daily and weekly basis (or other appropriate 
aggregate methodologies).  
 
The analysis of the primary endpoint will be performed based on the ITT and PP data sets. 
 
10.4.3 
ANALYSIS OF THE SECONDARY ENDPOINTS 
 
Secondary Endpoints include: 
• 
Safety as assessed by the incidence, seriousness, and severity of AEs. 
• 
Time to disease control by treatment day/week. 
• 
Time to rescue therapy by treatment day/week. 
• 
Change from baseline in BPDAI score by treatment week and at disease control. 
• 
Change from baseline in pruritus as evaluated by the BPDAI-VAS by treatment week and at disease 
control. 
• 
Change from baseline in skin biopsy 
 levels at disease control. 
• 
Evaluation of total cumulative steroid exposure at baseline, by treatment week, and at disease control. 
• 
Evaluation of maximum daily steroid dose at baseline, by treatment week, and at disease control. 
 
Safety data will be analyzed using the Safety Evaluable set. Treatment emergent AEs will be summarized by 

 
 
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MedDRA coding terms, and separate tabulations will be produced for treatment-related AEs, SAEs, and 
discontinuations due to AEs. 
 
Secondary efficacy measures will be analyzed using the ITT data set. 
 
Time to disease control will be compared between treatment groups by treatment day and week using a 
Kaplan-Meier curve. 
 
Time to rescue therapy will be compared between treatment groups by treatment day and week using a 
Kaplan-Meier curve. 
 
Change from baseline in BPDAI and BPDAI-VAS scores by treatment week until disease control will be 
compared between treatment groups using Student’s t-test. Missing values will not be estimated. 
 
Change from baseline in skin biopsy 
 levels at baseline (i.e., screening) and at disease control will 
be compared between treatment groups using Student’s t-test. 
 
Evaluation of total cumulative steroid exposure at baseline, by treatment week and at disease control will be 
summarized between treatment groups. A similar summarization for the maximum daily steroid dose until 
disease control will also be done. 
 
Additional safety data will be analyzed using the safety evaluable data set. Vital sign data and findings from 
physical examinations will be tabulated for changes over time during the study period. Laboratory parameters 
will be summarized for changes across the study period using descriptive statistics. 
 
10.4.4 
PLANNED INTERIM ANALYSES 
 
There is no planned interim analysis for this study. 
 
10.4.5 
MULTIPLE COMPARISON/MULTIPLICITY 
 
No adjustments for multiplicity will be employed.  
 
10.4.6 
EXPLORATORY ANALYSES 
 
The exploratory endpoints are: 
• Change from baseline in blister fluid protein levels 
 at treatment Week 1. 
• Change from baseline in blood 
 levels by treatment week and at disease control. 
• Change from baseline in Anti-BP180 IgG serum levels by treatment week and at disease control. 
• Evaluations of CBC, blood chemistry, and serum protein levels 
 
 at baseline, by study week and at disease control. 
• Changes in AKST4290 plasma concentrations at various timepoints. 
• Change from baseline in cognitive assessments using the MoCA at disease control. 
• Change from baseline in quality of life, as assessed by the DLQI at disease control. 
• Evaluation of exploratory biomarkers in plasma samples at various timepoints. 
 
Exploratory endpoints will be summarized descriptively. Treatment comparisons may be performed on 
exploratory endpoints to assist in the generation of hypotheses for future studies. 

 
 
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10.5 SAMPLE SIZE 
 
The sample size of 30 subjects was chosen based on clinical experience. 
 
10.6 MEASURES TO MINIMIZE BIAS 
 
10.6.1 
ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES 
 
To minimize the potential bias at the time of randomization, the study will be double-blinded and randomized 
in a 1:1 ratio (AKST4290:placebo). The randomization codes will be generated by a statistician that has no 
involvement in the study other than generation and maintenance of the randomization codes. 
 
10.6.2 
EVALUATION OF SUCCESS OF BLINDING 
 
Success of blinding will be assessed based on all occurrences (intentional or unintentional) of unblinding of 
blinded study subjects or study personnel (e.g., investigators, medical providers, cognitive/motor testing 
raters, the Sponsor or their representatives). All intentional and unintentional unblinding will be documented 
and reported to the Sponsor within 24 hours after notification of unblinding. 
 
10.6.3 
BREAKING THE STUDY BLIND/SUBJECT CODE 
 
The study blind can only be broken for safety reasons if the information is required for the management of 
SAEs, severe AEs, or pregnancies. Any noted intentional or unintentional breaking of the blind should be 
reported to the Sponsor’s Study Team Lead and QA function within 24 hours of notification of the unblinding 
event. If unintentional unblinding occurs during the study, root cause analysis will occur, and corrective and 
preventative actions will be documented and implemented. 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
Each participating site will maintain appropriate medical and research records for this trial, in compliance with 
ICH E6 R2 and regulatory and Institutional requirements for the protection of confidentiality of subjects. Each site 
will permit authorized representatives of regulatory agencies, the IRB/IEC, the Sponsor, or the Sponsor’s 
representatives to examine (and when permitted by applicable law, to copy) clinical records for the purposes of QA 
reviews, audits, and evaluation of the study safety, progress, and data validity. 
 
Source data are all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial. Examples of these original documents and data 
records include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, 
subject’s memory aids or evaluation checklists, pharmacy dispensing records, recorded audio tapes of counseling 
sessions, recorded data from automated instruments, copies or transcriptions certified after verification as being 
attributable, legible, accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, 
x-rays, and subject files and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
 
It is not acceptable for the CRF to be the only record of a subject’s participation in the study. This is to ensure that 
anyone who would access the subject’s medical record has adequate knowledge that the subject is participating in a 
clinical trial. Source document templates will be developed for this study. 

 
 
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12 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 ETHICAL STANDARD 
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the Protection of 
Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, ICH E6 R2, 21 CFR 
part 320, Retention of Bioavailability and Bioequivalence Testing Samples (1993), and the Declaration of 
Helsinki. 
 
12.2 INSTITUTIONAL REVIEW BOARD 
 
This protocol and any accompanying material to be provided to the subject (such as advertisements, subject 
information sheets, or descriptions of the study used to obtain informed consent) will be submitted by the 
investigator to an IRB or IEC. Approval from the IRB/IEC must be obtained before starting the study and should 
be documented in a letter to the investigator specifying the protocol number, protocol version, documents 
reviewed, and date on which the committee met and granted the approval. 
 
All changes to the consent form will be IRB/IEC approved; a determination will be made regarding whether 
previously consented subjects need to be re-consented. 
Any modifications or amendments to the protocol must also be submitted to the IRB/IEC for approval prior to 
implementation. 
 
12.3 INFORMED CONSENT PROCESS 
 
12.3.1 
CONSENT FORMS 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the subject or 
healthcare power of attorney or equivalent legal representative, and written documentation of informed 
consent is required prior to any study-related procedures. 
 
12.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
It is the responsibility of the investigator or designee to obtain written informed consent from each subject 
participating in this study after adequate explanation of the aims, methods, objectives, and potential hazards 
of the study and prior to undertaking any study-related procedures. 
 
Subjects should have the opportunity to discuss the study with their family members or other advisors and the 
time to consider participation in the trial carefully. The subjects may withdraw consent at any time throughout 
the course of the trial. 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. 
 
The investigator or designee must utilize an IRB/IEC approved consent form that contains the elements 
required by ICH GCP and applicable regulatory requirements for documenting written informed consent. 
Each informed consent will be appropriately signed and dated by the subject and the person obtaining 
consent. A copy of the signed consent form will be provided to the subject. By signing the informed consent 
form, all parties agree they will complete the evaluations required by the study, unless they withdraw 

 
 
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voluntarily or are terminated from the study for any reason. 
 
Investigators will be expected to maintain a screening log of all potential study candidates that includes 
limited information about the potential candidate (e.g., date of screening). 
 
All subjects who provide consent will be assigned a unique study number. This number will be used to 
identify the subject throughout the clinical study and must be used on all study documentation related to the 
study subject. Once a number is assigned to a subject, that number will remain with that study subject and 
will not be reused. 
 
If an individual’s medical chart or results of diagnostic tests performed as part of an individual’s regular 
medical care are going to be used for screening, written informed consent must be obtained prior to review of 
that information in accordance with Health Insurance Portability and Accountability Act. 
 
12.4 PARTICIPANT AND DATA CONFIDENTIALITY 
 
Subject confidentiality is held in strict trust by the participating investigators, their staff, the Sponsor, and their 
agents. This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the 
clinical information relating to subjects. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or data will be 
released to any unauthorized third party without prior written approval of the Sponsor. 
 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB/IEC, or 
government regulatory agencies may inspect 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 subjects in 
this study. The clinical study site will permit access to such records. 
 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their identities are 
protected from unauthorized parties. An identification code (i.e., not names) should be recorded on non-local lab 
samples, requisitions, and any documents submitted to the CRO, Sponsor, and/or IRB/IEC. The investigator must 
keep a subject log showing codes, names, and addresses for all subjects screened and for all subjects enrolled in 
the trial. The study subject’s contact information will be securely stored at each 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 local IRB/IEC and Institutional regulations. 
 
12.5 FUTURE USE OF STORED SPECIMENS 
 
With the subject’s approval and as approved by local IRB/IECs, de-identified biological samples may be stored at 
Alkahest, or designee, for future use. These samples could be used for research and to improve treatment. 
Alkahest will also be provided with a code-link that will allow linking the biological specimens with the specific 
data from each subject, maintaining the masking of the identity of the study subject. Subjects may choose whether 
the Sponsor can store and use samples for further research. 
 
During the conduct of the study, an individual subject can choose to withdraw consent to have biological 
specimens stored for future research.  
 
When the study is completed, access to study data and/or samples will be managed by Alkahest. In the event 
Alkahest transfers ownership to another commercial Sponsor, ownership of the samples may be transferred as 
well. 

 
 
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13 
DATA HANDLING AND RECORD KEEPING 
13.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, and timeliness of the data 
reported. 
 
Source documents provide evidence for the existence of the subject and substantiate the integrity of the data 
collected. Source documents are filed at the investigator’s site. Data entered in the eCRFs that are transcribed 
from source documents must be consistent with the source documents or the discrepancies must be explained. All 
source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. Black 
or blue ink is required to ensure clarity of reproduced copies. When making changes or corrections, cross out the 
original entry with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. The investigator may need to request previous medical 
records or transfer records, depending on the trial; also, current medical records must be available. 
 
For each subject who receives the study agent or placebo, the eCRF must be completed in a timely manner. The 
investigator will review and approve the eCRF for each study subject after all data have been entered, the eCRFs 
have been source document verified, and all queries have been resolved. This also applies to records for those 
subjects who fail to complete the study. If a subject withdraws from the study, the reason must be noted on the 
eCRF. If a subject is withdrawn from the study because of an AE, thorough efforts should be made to clearly 
document the outcome. 
 
All data collection and recordkeeping procedures must be compliant with applicable ICH GCP. 
 
13.1.1 
INVESTIGATOR RESPONSIBILITIES 
 
The investigator will comply with the protocol (which has been approved/given favorable opinion by an 
IRB/IEC), ICH GCP, and applicable regulatory requirements. The investigator is ultimately responsible for 
the conduct of all aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the Sponsor. The term “investigator” as used in this protocol as well as in other study 
documents, refers to the investigator or authorized study personnel that the investigator has designated to 
perform certain duties. Sub-investigators as listed on Form FDA 1572 or other authorized study personnel are 
eligible to sign for the investigator, except where the investigator’s signature is specifically required. 
 
13.1.2 
STUDY FILES 
 
The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented and the study data to be subsequently verified. These documents should be classified into 
2 separate categories (although not limited to) the following: (1) investigator’s study file, and (2) subject 
clinical source documents. 
 
The investigator’s study file will contain the clinical study protocol/amendments, Investigator’s Brochure 
(IB), eCRF, IRB/IEC approval with correspondence, informed consents, drug records, staff curriculum vitae 
and authorization forms, and other appropriate documents and study specific manuals (e.g., Laboratory 
Manual). 
 

 
 
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Subject clinical source documents would include (although are not limited to) the following: subject 
hospital/clinic records, physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, 
radiologic imaging, x-ray, pathology and special assessment reports, consultant letters, screening and 
enrollment log, etc. 
 
13.2 STUDY RECORDS RETENTION 
 
All clinical study documents must be retained by the investigator until 2 years after the study is discontinued and 
regulatory authorities have been notified. Before the investigator destroys any material related to the clinical 
study, he/she must obtain approval in writing from the Sponsor. 
 
The investigator should keep a file where the full name and address of the subject and all signed informed 
consents are included for at least 15 years after completion of the trial. Any original study-related information that 
permits verification of inclusion and exclusion criteria, including clinical history, a copy of all data collection 
logs, and documents on the use of the study agent, must be stored for as long a time period as permitted by the 
center. 
 
Should the investigator wish to move study records to another location, arrangements must be made to store these 
in sealed containers so that they can be returned sealed to the investigator in case of a regulatory audit. Where 
source documents are required for the continued care of the subject, appropriate copies should be made for storage 
outside of the site. 
 
13.3 PROTOCOL DEVIATIONS 
 
A Protocol Deviation is any noncompliance with the clinical trial protocol or with GCP. The noncompliance may 
be either on the part of the subject, the investigator, or the study site staff. When deviations occur, corrective 
actions are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
Protocol Deviations will be categorized as either Major or Minor and will be defined in the study specific 
Protocol Deviation Plan. 
 
Major Protocol Deviations are departures from the approved protocol relating to the conduct of the study 
which may affect the rights, safety, and/or wellbeing of study participants or the study outcomes or data 
quality. Major protocol deviations may result in data that are not deemed evaluable for the PP analysis and/or 
may require that subjects are discontinued from the study. Major protocol deviations are Significant Clinical 
Issues. Note: observations categorized as Major may include those situations where there is a pattern of 
deviation, numerous Minor observations, or other significant deviation. 
 
Minor Protocol Deviations are departures from the approved protocol relating to the conduct of a study that 
does not affect the rights, safety, and/or wellbeing of study participants or the study outcomes or data quality. 
Minor protocol deviations would not generally preclude subject data from the PP analysis population. 
Note: persistently missed or incomplete study procedures and/or study evaluations will be considered Major 
protocol deviations. 

 
 
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All deviations will be logged and tracked by the site and CRO. Periodic review of Protocol Deviations will serve as 
an indicator of site performance. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations promptly to the study 
CRO and/or Sponsor. All deviations must be addressed in study source documents. Notification of Protocol 
Deviations must be sent to the local IRB/IEC per their guidelines. The site investigator/study staff is responsible 
for knowing and adhering to their IRB/IEC requirements. 
 
13.4 PUBLICATION AND DATA SHARING POLICY 
 
In compliance with The International Committee of Medical Journal Editors clinical trials registration policy and 
Section 801 of the FDA Amendments Act of 2007, this study will be registered by the Sponsor in 
ClinicalTrials.gov, a public trials registry which is sponsored by the National Library of Medicine. 
 
Notwithstanding the Sponsor’s requirements for registration and data sharing in ClinicalTrials.gov, any formal 
presentation or publication of data collected as a direct or indirect result of this trial will be considered as a joint 
publication by the investigator(s) and the Sponsor. In the case of multicenter studies, it is mandatory that the first 
publication be made based on the totality of data obtained from all centers, analyzed as stipulated in the protocol, 
and presented and interpreted as documented in the final Clinical Study Report. The resulting publication will 
name investigators according to the policy of the chosen journal. Where it is not permitted for all investigators to 
be included as authors, the publication will name all investigators within the publication. 
 
Individual investigators may publish data arising from their own subjects. The investigator will provide the 
Sponsor with copies of written publications (including abstracts and posters) at least 60 days in advance of 
submission. This review is to permit the Sponsor to review the communication for accuracy (thus avoiding 
potential discrepancies with submissions to regulatory authorities), to verify that confidential information is not 
inadvertently divulged (including patent protection), to allow adequate input or supplementary information that 
may not have been available to the investigator, and to allow establishment of co-authorship. 
 
Investigators participating in multicenter studies must agree not to engage in presentations based on data gathered 
individually or by a subgroup of centers before publication of the first main publication unless this has been 
agreed otherwise by all other investigators and the Sponsor. However, in the event that no publication of the 
overall results has been submitted after approval of the Clinical Study Report, investigators may publish results of 
one or more center’s subjects to the same review as outlined above. The Sponsor will circulate proposed 
multicenter publications to all investigators for review. 
 
Data will be reviewed by all participating investigators prior to publication. The study Sponsor will have 90 days 
to review all definitive publications, such as manuscripts and book chapters, and a minimum of 30 days to review 
all abstracts. 
 
14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY 
 
A separate financial disclosure agreement will be made between each principal investigator and Alkahest, Inc. or 
its authorized representative before the study agent is shipped. Each investigator will notify Alkahest, Inc. or its 
authorized representative of any relevant changes during the conduct of the study and for 1 year after the study 
has been completed. Alkahest and the study CRO will evaluate any disclosed conflicts of interest and will 
establish a mechanism for their management. 
 

 
 
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15  
SCHEDULE OF EVENTS 
 
Screening/ 
Baseline 
Treatment 
EOT 
Safety  
Follow-up6 
Visit Number/Name 
Day 
Window (days) 
Week 
1 
-3 to 0 
2 
1 
 
31 
7 
±2 
1 
42 
14 
±2 
2 
Unsched. 
Visit4 
53/ EOT5   
21 or Dis. Control 
±23 
Up to 3 
Follow-up 
EOT + 14  
±3 
Up to 5 
Informed consent7 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X8 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
 
Targeted physical examination 
 
X 
X 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
X 
 
BPDAI 
X 
X 
X 
X 
 
X 
 
BPDAI-VAS 
X 
X 
X 
X 
 
X 
 
Skin biopsy9 
X 
 
 
 
 
X 
 
Blister fluid collection 
 
X 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Topical steroid assessment10 
 
X 
 
 
X 
 
 
Administration of study agent 
 
 
 
Administration of topical steroid 
therapy 
 
 
 
Assessment of disease control11 
 
 
X 
X 
X 
X 
 
Rescue therapy assessment12 
 
 
X 
X 
X 
 
 
MoCA 
 
X 
 
 
 
X 
 
DLQI 
 
X 
 
 
 
X 
 
Laboratory tests13 
X 
X 
X 
X 
 
X 
 
Serum protein sample collection 
X 
X 
X 
X 
 
X 
 
Anti-BP180 antibodies sample  
collection 
X 
X 
X 
X 
 
X 
 
Pregnancy test (in WOCBP only)14 
X 
 
 
 
 
X 
 
PK blood sample15 
 
X 
X 
X 
 
X 
 
Biomarker plasma aliquots16 
 
X 
 
 
 
X 
 
Study agent accountability17 
 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications18 
X 
X 
X 
X 
X 
X 
X 
Documentation of confirmation of 
histological BP diagnosis 
 
 
 
 
 
X 
 
Trial completion 
 
 
 
 
 
 
X 

 
 
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17 
APPENDICES 
 
The BP assessments, cognitive assessment and quality of life assessment tools provided in this section and 
associated information are provided as EXAMPLES ONLY. The actual assessments, related source documents, 
and instructions for administration and scoring are included in a rater reference manual or equivalent. 
 
 
 

 
 
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17.1 BULLOUS PEMPHIGOID DISEASE AREA INDEX TOOL 
 

 
 
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17.2 BULLOUS PEMPHIGOID DISEASE AREA INDEX TOOL - VISUAL ANALOG SCALE 
 
 
 
 

 
 
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PRURITIS ASSESSMENT FOR BP PATIENTS 
WITH IMPAIRED MENTAL FUNCTIONING: 
 
 

 
 
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17.3 DERMATOLOGY LIFE QUALITY INDEX 
 
 
 

 
 
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17.4 MONTREAL COGNITIVE ASSESSMENT 
 
The MoCA (Nasreddine 2005) is a commonly used screening test easily administered by nonspecialist staff. It 
assesses the domains of attention and concentration, executive functions, memory, language, visuoconstructional 
skills, conceptual thinking, calculations, and orientation. The total possible score is 30 points with a score of 26 or 
more considered normal. Time to administer the MoCA is approximately 15 minutes. The total possible score is 
30 points. 
 
 
 
 

 
 
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17.5 MODIFICATION OF DIET IN RENAL DISEASE FORMULA 
 
The GFR may be estimated based on the MDRD formula: 
 
 
 
Units: GFR [ml/min], age [years] 
 
 
 
 

 
 
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17.7 CLINICAL EVALUATION OF LIVER INJURY 
 
17.7.1 
INTRODUCTION 
 
Alterations of liver laboratory parameters
 
 are to be 
further evaluated using the procedures described below. 
 
17.7.2 
PROCEDURES 
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 to 72 hours and 
provide additional blood sample to the central laboratory for automatic reflex testing of the below listed 
laboratory parameters. Only in cases in which the central laboratory is not immediately available (e.g. if the 
logistics are such that the subject´s repeat specimen would not reach the central laboratory in a reasonable 
timeframe), ALT, AST, and bilirubin (total and direct) will be evaluated by the local laboratory and results 
will be made available to the investigator and to Alkahest as soon as possible. If ALT and/or AST > 3-fold 
ULN combined with an elevation of total bilirubin >2-fold ULN are confirmed, results of the laboratory 
parameters described below must be made available to the investigator and to Alkahest as soon as possible. 
 
In addition, the following should be reported in the eCRF: 
• 
Detailed history of current symptoms and concurrent diagnoses and medical history according to the 
DILI Checklist provided in the ISF 
• 
History of concomitant drug use (including non-prescription medications, herbal and dietary 
supplement preparations), alcohol use, recreational drug use, and special diets according to the DILI 
Checklist provided in the ISF 
• 
History of exposure to environmental chemical agents (consider home and workplace exposure) 
according to the DILI Checklist provided in the ISF 
 
17.10.2.1  Clinical Chemistry 
• 
Obtain an ALP, albumin, prothrombin time or INR, creatinine kinase, creatinine kinase-muscle/brain 
test, ceruloplasmin, α-1 antitrypsin, transferrin amylase, lipase, glucose, cholesterol, triglycerides 
 
17.10.2.2  Serology 
• 
Obtain a hepatitis A (anti-immunoglobulin M [IgM], anti-IGM), hepatitis B (hepatitis B antigen, anti-
HBs, DNA), hepatitis C (anti-hepatitis C virus [HCV], RNA if anti-HCV positive), hepatitis D (anti-
IgM, anti-immunoglobulin G [IgG]), hepatitis E (anti-hepatitis E virus [HEV], anti-HEV IgM, RNA if 
anti-HEV IgM positive), anti-smooth muscle antibody (titer), anti-nuclear antibody (titer), anti-liver-
kidney microsomes antibody, antimitochondrial antibody, Epstein Barr virus (vascularized composite 
allotransplantation [VCA] IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, 
IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis (IgG, IgM). 
 
17.10.2.3  Hormones 
• 
Thyroid-stimulating hormone 
 
17.10.2.4  Hematology 
• 
Thrombocytes, 
 
 

 
 
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17.10.2.5  Ultrasound 
• 
Provide an abdominal ultrasound to rule out biliary tract, pancreatic, or intrahepatic pathology 
(e.g., bile duct stones or neoplasm) 
 
17.10.2.6 Observation/Repeat Testing 
• 
Initiate close observation of subjects by repeat testing of ALT, AST, and total bilirubin (with 
fractionation by total and direct) at least weekly until the laboratory ALT and/or AST abnormalities 
stabilize or return to normal, then according to the protocol. Depending on further laboratory changes, 
additional parameters identified e.g. by reflex testing will be followed up based on medical judgment 
and GCP. 
 

 
 
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17.8 PHARMACOKINETIC AND BIOMARKER SAMPLING 
 
17.8.1 
TABLE OF PHARMACOKINETIC AND BIOMARKER SAMPLING 
 
Visit 
Time Point 
Time for 
Database Setup 
PK 
Blood 
Extra Biomarker Aliquot 
from PK Blood Sample 
2 (Baseline) 
Prior to (i.e., within 15 min before 
study agent administration) 
REQUIRED SAMPLE 
-0:15 h 
X 
X 
0:00 
0:00 h 
Study agent administration 
1:00 hour  ± 15 minutes after 
administration of the first dose 
REQUIRED SAMPLE 
1:00 h 
X 
 
2 ± 30 minutes after administration 
of the first dose 
OPTIONAL SAMPLE 
2:00 h 
X 
 
4 ± 30 minutes after administration 
of the first dose 
OPTIONAL SAMPLE 
4:00 h 
X 
 
3 – 5 (Study 
Week 1 and all 
subsequent 
weekly visits 
until EOT) 
-00:15 min (i.e., within 15 min 
before study agent administration) 
 
X 
 
EOT 
Any time during visit – preferably 
at the end of all visit procedures 
 
X 
X 
 

 
 
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17.9 PHARMACOKINETIC MEASURES AND EVALUATION 
 
17.9.1 
TIMING OF PHARMACOKINETIC BLOOD SAMPLING 
For the time schedules of PK blood samples, please refer to Section 17.8.1. 
 
17.9.2 
PHARMACOKINETIC SAMPLE HANDLING AND SHIPMENT 
Methods of PK sample collection are described in Section 7.2.2.1.2. Further instructions for sampling 
procedures, and for handling, storage and shipment of the samples will be provided in the Laboratory Manual 
in the ISF. 
 
17.9.3 
PHARMACOKINETIC DATA EVALUATION 
For PK analysis and displays, concentrations will be presented in the same format as reported in the 
bioanalytical report. Only concentrations within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. 
 
17.9.4 
HANDLING OF MISSING BIOANALYTICAL DATA 
In the noncompartmental analysis, concentration data identified as no sample available (NOS), no valid 
results (NOR), or not analyzed (NOA) will not be considered. Below limit of quantification (BLQ) and NOP 
values in the lag phase will be set to zero. The lag phase is defined as the period between time zero and the 
first timepoint with a concentration above the quantification limit. All other BLQ and/or NOP values of the 
profile will be ignored. Every effort will be made to include all concentration data in an analysis. If not 
possible, a case to case decision is required whether the value should be excluded. 
Descriptive statistics of concentrations will be calculated only when at least 2/3 of the individuals have 
concentrations within the validated concentration range. The overall sample size to decide whether the '2/3' 
rule is fulfilled will be based on the total number of samples intended to be drawn for that time point 
(i.e., BLQ, NOR, NOS, NOA, NOP are included). Descriptive statistics of parameters are calculated only 
when at least 2/3 of the individual parameter estimates of a certain parameter are available.