Clinical Trial Protocol: DX-2930-03

Study Title:	HELP Study : A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate DX-2930 For Long-Term Prophylaxis Against Acute Attacks of Hereditary Angioedema (HAE)
Study Number:	DX-2930-03
Study Phase:	Phase 3
Product Name:	DX-2930
IND Number:	116647
EudraCT Number:	2015-003943-20
Indication:	Prevention of angioedema attacks in patients with HAE
Investigators:	Multicenter
Sponsor:	Dyax Corp. 55 Network Drive, Burlington, MA 01803 USA
Sponsor Contact:	Ryan Iarrobino PPD , Clinical Development 55 Network Drive, Burlington, MA 01803 USA Phone: PPD
Medical Monitor US and Canada:	PPD , M.D. Voisin Consulting Phone: PPD
	Date:
	Original Protocol
	Confidentiality Statement

PROTOCOL SIGNATURE PAGE

SYNOPSIS

Run-In Period:

Treatment Period:

Criteria for Inclusion:

1. Males and females 12 years of age or older at the time of screening.
2. Documented diagnosis of HAE (Type I or II) based upon all of the following:

• Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling episodes without accompanying urticaria).
• Diagnostic testing results obtained during screening (or a prior DX-2930 study) that confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level of the normal level. Subjects with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range. Subjects may begin participating in the run-in period before these diagnostic results are available. Subjects may be retested if results are incongruent with clinical history or believed by the Investigator to be confounded by recent LTP use.
• At least one of the following: Age at reported onset of first angioedema symptoms years, a family history consistent with HAE Type I or II, or C1q within normal range.

3. Experiencing a baseline rate of at least 1 Investigator-confirmed HAE attack per 4 weeks as confirmed during the run-in period.
4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, understand, and sign an informed consent form. Subjects age 12 to 17, whose caregiver provides informed consent, are willing and able to read, understand and sign an assent form.
5. Males and females who are fertile and sexually active must adhere to contraception requirements for the duration of the study as follows:

• Females of childbearing potential must agree to be abstinent or else use any two of the following medically acceptable forms of contraception from screening through 30 days after the final study visit: progestin-only oral contraceptive, condom with or without spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intrauterine device (IUD, all types). A female whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception.
• Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months do not require contraception during the study.
• Males, including males who are surgically sterile (post vasectomy), with female partners of childbearing potential must agree to be abstinent or else use a medically acceptable form of contraception from screening through 60 days after the final study visit.

Criteria for Exclusion:

1. Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), idiopathic angioedema, or recurrent angioedema associated with urticaria.
2. Dosing with an investigational drug or exposure to an investigational device within 4 weeks prior to screening.
3. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
4. Exposure to androgens (e.g. stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) within 2 weeks prior to entering the run-in period.
5. Use of long-term prophylactic therapy for HAE (C1-INH, attenuated androgens, or antifibrinolytics) within 2 weeks prior to entering the run-in period.
6. Use of short-term prophylaxis for HAE within 7 days prior to entering the run-in period. Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics used to avoid angioedema complications from medically indicated procedures.
7. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3x upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of normal, or total bilirubin upper limit of normal (unless the bilirubin elevation is a result of Gilbert's syndrome).
8. Pregnancy or breastfeeding.
9. Subject has any condition that, in the opinion of the Investigator or Sponsor, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results (e.g., history of substance abuse or dependence, significant pre-existing illness or other major comorbidity that the Investigator considers may confound the interpretation of study results).

Test Product; Dose; and Mode of Administration:

Placebo; Dose; and Mode of Administration:

Duration of Treatment:

Duration of Study for Individual Subjects:

Prohibited Concomitant Treatments:

• Long-term prophylaxis for HAE (e.g., use of C1-INH for long-term prophylaxis, attenuated androgens, or anti-fibrinolytics).
• Angiotensin-converting enzyme (ACE) inhibitors.
• Estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy).
• Androgens (e.g., stanozolol, danazol, oxandrolone, methyltestosterone, testosterone).
• Any other investigational drug or device.

Management of Acute Attacks:

Safety Assessments:

• Adverse events (AEs), including serious adverse events (SAEs) and adverse events of
  special interest (AESI).
• Vital signs, including sitting or supine blood pressure (BP), heart rate (HR), body temperature, and respiratory rate (RR).
• Physical examination.
• Clinical laboratory testing (hematology, serum chemistry, coagulation, and urinalysis).
• 12-Lead electrocardiogram (ECG).

Pharmacokinetic (PK) Assessments:

Pharmacodynamic (PD) Assessments:

Immunogenicity Assessments:

C1-INH, C4 and C1q Assessments:

Quality of Life Assessments:

Collection of HAE Attack Data:

• Date and time symptoms of an attack were first experienced
• Description of symptoms experienced, including location(s)
• Impact on activity and whether any assistance or medical intervention was required, including hospitalizations or emergency department visits
• Any medications used to treat the attack
• If the attack resolved, date and time the subject was no longer experiencing symptoms

• Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region
• Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea
• Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx

Study Stopping Rules:

Individual Stopping Rules:

Criteria for Evaluation:

Primary Endpoint

• Number of HAE attacks per week

Secondary Endpoints (rank ordered)

1. Time to first attack, i.e. duration that a subject is attack-free until their first attack.
2. Number per week of HAE attacks requiring acute attack therapy use.
3. Number per week of moderate or severe HAE attacks.
4. Number per week of high-morbidity HAE attacks; a high-morbidity HAE attack is defined as any attack that has at least one of the following characteristics: severe, results in hospitalization (except hospitalization for observation hours), hemodynamically significant (systolic blood pressure , requires IV hydration, or associated with syncope or nearsyncope) or laryngeal.

Safety Measures:

• Adverse events (AEs) including serious adverse events (SAEs) and adverse events of special interest (AESI)
• Clinical laboratory testing (hematology, clinical chemistry, coagulation and urinalysis)
• Vitals signs including blood pressure, heart rate, body temperature and respiratory rate
• Physical examination
• 12-lead electrocardiogram (ECG)

Additional Measures:

• Pharmacodynamic effects
• Anti-drug antibody development
• Pharmacokinetic parameter determinations
• Quality of life assessments

Analysis Populations:

Sample Size Determination:

Statistical Methods:

Safety Analysis:

TABLE OF CONTENTS

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

1 INTRODUCTION

1.1 DX-2930

1.2 Hereditary Angioedema

1.3 Therapeutic Rationale for DX-2930

1.4 Safety Rationale for DX-2930

1.5 DX-2930 Non-Clinical Pharmacology and Toxicology

1.6 DX-2930 Clinical Data

1.6.1 Single-Ascending Dose Study in Healthy Subjects (DX-2930-01)

1.6.2 Multiple-Ascending Dose Study in HAE Patients (DX-2930-02)

2 STUDY OBJECTIVES

2.1 Primary Objective

2.2 Secondary Objective

2.3 Tertiary Objectives

• To evaluate the pharmacodynamic (PD) effects of chronically administered DX-2930
• To assess the immunogenicity of chronically administered DX-2930
• To evaluate the pharmacokinetics (PK) of chronically administered DX-2930
• To evaluate the effect of DX-2930 upon quality of life assessments

3 INVESTIGATIONAL PLAN

3.1 Overall Study Design and Plan

3.1.1 Overview

Long-Term Prophylactic (LTP) Therapy Washout:

Run-In Period:

Treatment Period:

Open-Label Extension (OLE):

Figure 1. Overview of the Study Design

Follow-up Period:

3.1.2 Safety Oversight and Stopping Rules

3.1.2.1 Study Safety Committee (SSC)

• Suspension of dosing in the study
• Suspension of dosing in a specific dosing arm
• Increase in subject post-dose monitoring period at the study site

3.1.2.2 Study Level Stopping Rules

3.1.2.3 Individual Stopping Rules

3.1.3 Follow-up for Subjects Meeting Stopping Criteria

• Additional clinical laboratory tests and/or other clinical investigations
• Additional visits or extended duration of follow-up
• Obtaining a specialist consultation

3.2 Rationale for Pivotal Dose Selection

3.3 Individual Subject Dosing and Follow-Up

3.4 Study Duration for Individual Subjects

4 STUDY POPULATION SELECTION

4.1 Study Population

4.2 Inclusion Criteria

1. Males and females 12 years of age or older at the time of screening.
2. Documented diagnosis of HAE (Type I or II) based upon all of the following:

• Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling episodes without accompanying urticaria).
• Diagnostic testing results obtained during screening (or a prior DX-2930 study) that confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level of the normal level. Subjects with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range. Subjects may begin participating in the run-in period before these diagnostic results are available. Subjects may be retested if results are incongruent with clinical history or believed by the Investigator to be confounded by recent LTP use.
• At least one of the following: age at reported onset of first angioedema symptoms years, a family history consistent with HAE Type I or II, or C1q within normal range.

3. Experiencing a baseline rate of at least 1 Investigator-confirmed HAE attack per 4 weeks as confirmed during the run-in period.
4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, understand, and sign an informed consent form. Subjects age 12 to 17, whose caregiver provides informed consent, are willing and able to read, understand and sign an assent form.
5. Males and females who are fertile and sexually active must adhere to contraception requirements for the duration of the study as follows:

• Females of childbearing potential must agree to be abstinent or else use any two of the following medically acceptable forms of contraception from screening through 30 days after the final study visit: progestin-only oral contraceptive, condom with or without spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intrauterine device (IUD, all types). A female whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception.
• Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months do not require contraception during the study.
• Males, including males who are surgically sterile (post vasectomy), with female partners of childbearing potential must agree to be abstinent or else use a medically acceptable form of contraception from screening through 60 days after the final study visit.

4.3 Exclusion Criteria

1. Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), idiopathic angioedema, or recurrent angioedema associated with urticaria.
2. Dosing with an investigational drug or exposure to an investigational device within 4 weeks prior screening.
3. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
4. Exposure to androgens (e.g. stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) within 2 weeks prior to entering the run-in period.
5. Use of long-term prophylactic therapy for HAE (C1-INH, attenuated androgens, or antifibrinolytics) within 2 weeks prior to entering the run-in period.
6. Use of short-term prophylaxis for HAE within 7 days prior to entering the run-in period. Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics used to avoid angioedema complications from medically indicated procedures.
7. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) upper limit of normal, or aspartate aminotransferase (AST) upper limit of normal, or total bilirubin upper limit of normal (unless the bilirubin elevation is a result of Gilbert's syndrome).
8. Pregnancy or breastfeeding.
9. Subject has any condition that, in the opinion of the Investigator or Sponsor, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results (e.g., history of substance abuse or dependence, significant pre-existing illness or other major comorbidity that the Investigator considers may confound the interpretation of study results).

5 STUDY TREATMENT(S)

5.1 Description of Treatment(s)

5.1.2 Placebo

5.2 Dosing and Follow-Up Schedule

5.3 Method of Assigning Subjects to Treatment Groups

5.4 Blinding and Unblinding

5.5 Prior and Concomitant Therapy

5.5.1 Allowed Therapies

• Therapies for co-existing conditions, including those for acute attacks of HAE, are permitted if not excluded in Section 5.5.2.
• The use of short-term prophylactic treatment for HAE will be permitted if medically indicated.
• Therapies to treat any AEs the subject experiences during the study are permitted.

5.5.2 Excluded Concomitant Therapies

• Long-term prophylaxis for HAE (e.g., use of C1-INH for long-term prophylaxis, attenuated androgens, or anti-fibrinolytics).
• Angiotensin-converting enzyme (ACE) inhibitors.
• Estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy).
• Androgens (e.g., stanozolol, danazol, oxandrolone, methyltestosterone, testosterone).
• Any other investigational drug or device.

5.6 Restrictions

5.6.1 Medical Interventions

5.6.2 Fluid and Food Intake

5.6.3 Activity

5.7 Treatment Compliance

5.8 Packaging and Labeling

5.9 Storage and Accountability

5.10 Investigational Medicinal Product Retention at Study Site

6 STUDY PROCEDURES

6.1 Informed Consent

6.2 Eligibility Review

6.3 Demographics and Medical History

6.4 Efficacy Assessments

6.4.1 Primary and Secondary Endpoints

Primary Endpoint

• Number of HAE attacks per week

Secondary Endpoints (in rank order)

1. Time to first attack, i.e., duration that a subject is attack-free until their first attack.
2. Number per week of HAE attacks requiring acute attack therapy use.
3. Number per week of moderate or severe HAE attacks.
4. Number per week of high-morbidity HAE attacks; a high-morbidity HAE attack is defined as any attack that has at least one of the following characteristics: severe, results in hospitalization (except hospitalization for observation hours), hemodynamically

significant (systolic blood pressure , requires IV hydration, or associated with syncope or near-syncope) or laryngeal.

6.4.2 HAE Attack Information Collection

• Date and time symptoms of an attack were first experienced
• Description of symptoms experienced, including location(s)
• Impact on activity and whether any assistance or medical intervention was required, including hospitalizations or emergency department visits
• Any medications used to treat the attack
• If the attack resolved, date and time the subject was no longer experiencing symptoms

• Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region.
• Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea.
• Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx.

6.5 Vital Signs

6.6 Physical Examination

• Height and weight (at Screening visit only)
• General appearance
• Ears, nose, and throat
• Head and Neck
• Ophthalmological
• Respiratory
• Cardiovascular
• Abdomen
• Neurological
• Extremities
• Dermatological
• Lymphatic

6.7 Electrocardiography (ECG)

6.8 Clinical Laboratory Tests

6.8.1 Laboratory Parameters

6.8.1.1 Hematology

• Hemoglobin
• Hematocrit
• Red blood cell (RBC) count
• White blood cell (WBC) count with differential
• Mean corpuscular volume (MCV)
• Mean corpuscular hemoglobin (MCH)
• Mean corpuscular hemoglobin concentration (MCHC)
• Absolute platelet count
  6.8.1.2 Coagulation
• Prothrombin time (PT)
• Activated partial thromboplastin time (aPTT)
• International Normalized Ratio (INR)
  6.8.1.3 Chemistry
• Albumin
• Alkaline phosphatase
• Alanine aminotransferase (ALT; SGPT)
• Aspartate aminotransferase (AST; SGOT)
• Bilirubin (total and direct)
• Blood urea nitrogen (BUN)
• Calcium
• Carbon dioxide (CO2)
• Chloride
• Creatinine
• Creatine phosphokinase (CPK)
• Glucose
• Phosphate
• Magnesium
• Potassium
• Sodium
• Total protein
• Uric acid
  6.8.1.4 Urinalysis
• Bilirubin
• Glucose
• Ketones
• Blood
• Nitrite
• pH
• Protein
• Specific gravity
• Microscopy (if indicated by macroscopic findings)
  6.8.1.5 Serology

6.8.1.9 C1q Assay

6.8.1.10 PK Sample Collection

6.8.1.11 PD Sample Collection

6.8.1.12 Plasma Anti-Drug Antibody Testing

6.8.2 Sample Collection, Storage, and Shipping

6.9 Pharmacokinetic Assessments

6.10 Pharmacodynamic Assessments

6.11 Plasma Anti-Drug Antibody Testing

6.12 Prior and Concomitant Therapy

6.13 Randomization

6.14 Investigational Medicinal Product Treatment

6.15 Quality of Life Assessments

6.16 Adverse Event Reporting

6.16.1 Definitions

6.16.1.1 Adverse Event

• AEs may be new events or may be pre-existing conditions that have become aggravated or have worsened in severity or frequency during the course of the study.
• AEs may be clinically significant changes from baseline in physical examination, laboratory tests, or other diagnostic investigation (e.g., laboratory results, x-ray findings).

6.16.1.2 Serious Adverse Event

• Death
• Life-threatening experience; Note: "Life-threatening" refers to a situation in which the subject was at substantial risk of death at the time of the event; it does not refer to an event that might have caused death if it were more severe.
• Requires inpatient hospitalization or prolongation of existing hospitalization; Note: Does not include hospitalization for observation with release within 24 hours. A scheduled hospitalization for a pre-existing condition that has not worsened during participation in the study does not meet this criterion. Pre-planned hospitalizations for an elective medical/surgical procedure or routine check-ups do not meet this criterion.
• Results in persistent or significant disability or incapacity.
• Is a congenital anomaly or birth defect.
• Is considered to be an important medical event defined as those that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the subject or may require intervention to prevent one of the outcomes listed in the definition above.

6.16.1.3 Overdose

6.16.1.4 Planned Hospitalization

6.16.1.5 Treatment-Emergent Adverse Events (TEAE)

6.16.1.6 Adverse Events of Special Interest (AESI)

Hypersensitivity reactions

Events of Disordered Coagulation

Bleeding AESI

Hypercoagulable AESI

6.16.2 Monitoring

6.16.2.1 Monitoring of Adverse Events

• Subjects will be questioned and/or examined by the Investigator or a qualified designee for evidence of AEs. The questioning of subjects with regard to the possible occurrence of AEs will be generalized such as, "How have you been feeling since your last visit?" The presence or absence of specific AEs should not be elicited from subjects.
• Subjects having TEAEs will be monitored until resolution with relevant clinical assessments and laboratory tests, as determined by the Investigator.
• AEs, actions taken as a result of AEs, and follow-up results must be recorded in the eCRF as well as in the subject's source documentation. Follow-up laboratory results should be filed with the subject's source documentation.

6.16.2.2 Monitoring of Safety Laboratory Assessments

6.16.3 Assessment of Adverse Events

6.16.3.1 Assessment of Severity

• GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required
• GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be needed; no or minimal medical intervention/therapy required
• GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalizations possible
• GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance required; significant medical intervention/therapy required, hospitalization or hospice care probable

6.16.3.2 Assessment of Causality

• Possible alternative causes of the AE , including the disease under treatment, pre-existing conditions, concomitant use of other drugs, and presence of environmental or genetic factors.
• The temporal association between IMP exposure and onset of the AE.
• Whether the manifestations of the AE are consistent with known actions or toxicity of the IMP.
• The AE resolved or improved with decreasing the dose or stopping use of the IMP (dechallenge). Judgment should be used if multiple products are discontinued at the same time.

• Temporal relationship is lacking (e.g., the event did not occur within a reasonable time frame following administration of the IMP); or
• Other causative factors more likely explain the event (e.g., a pre-existing condition, other concomitant treatments).

• There is a positive temporal relationship (e.g., the event occurred within a reasonable time frame following administration of IMP); or
• The AE is more likely explained by the investigational product than by another cause (i.e., the AE shows a pattern consistent with previous knowledge of the investigational product or the class of the IMP).

6.16.3.3 Assessment of Clinical Significance

6.16.4 Clinical Laboratory Adverse Events

• APTT prolongation in the absence of any associated bleeding or other evidence of clinical relevance will not be considered a clinically significant laboratory abnormality or AE. In the appropriate physiologic setting, such as IV heparin therapy, aPTT can be used to monitor bleeding risk. However, as noted in the Investigators Brochure, aPTT prolongation due to plasma kallikrein inhibition is an artifactual in vitro phenomenon. Although plasma kallikrein drives fibrin formation in the aPTT assay, plasma kallikrein-driven coagulation does not appear to have hemostatic or other physiologically important functions in vivo. It is well documented that, in humans, deficiency of factor XII or prekallikrein (and thus plasma kallikrein) is not associated with abnormal bleeding, either spontaneous or during surgical procedures (Renne and Gruber, 2012). Despite the lack of clinical effect, deficiency of either protein is associated with marked prolongation of the aPTT .

6.16.5 Reporting Investigator Safety Observations to the Sponsor

6.16.5.1 Reporting Non-serious Adverse Events

6.16.5.2 Reporting Pregnancies

• SAE
• AESI
• Overdose
• Cancer

• Resolved with or without residual effects.
• A return to baseline for a pre-existing condition.
• Laboratory values have returned to baseline or stabilized.
• The Investigator does not expect any further improvement or worsening of the event.
• Fatal outcome-if an autopsy is performed, the autopsy report is requested to be provided to the sponsor as soon as it is available.
  6.16.5.4 Expedited Reporting by the Sponsor to a Regulatory Health Authority

6.16.5.5 Safety Contact Information

24-Hour Medical Safety Contact for Europe and Middle East
PPD , M.D.

PPD

Phone: PPD

Email: PPD

Dyax Pharmacovigilance Department

Contacts: PPD

Email: PPD

6.16.5.6 Safety Notifications by the Sponsor to the Investigator

6.16.5.7 Unblinding a Subject's Treatment during the Trial

6.17 Subject Withdrawal

• In the opinion of the Investigator, the subject is unable to comply with the requirements of the protocol for satisfactory completion or interpretation of study results,
• A serious or intolerable AE occurs,
• A clinically significant change in a laboratory parameter occurs,
• The Sponsor or Investigator terminates the study, or
• The subject requests to be discontinued from the study.

6.18 Appropriateness of Measurements

7 STUDY ACTIVITIES

7.1 Screening

The following procedures and assessments are to be performed during Screening:

• Informed consent (Section 6.1)
• Eligibility review (Section 6.2)
• Demographics and medical history (Section 6.3)
• C1-INH functional assay, C4 and C1q sample collection (Section 6.8)
• Pregnancy test, serum or urine (females) (Section 6.8)
• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Complete physical examination (Section 6.6); documentation of height and weight
• 12-Lead ECG (Section 6.7)
• Laboratory testing including, serology, hematology, coagulation, serum chemistry and urinalysis (Section 6.8)
• Prior and concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16); pre-existing signs and symptoms
• Subjects who are on LTP for HAE must complete a 2 week washout period, as confirmed by the Investigator, before entering the run-in period.

7.2 Run-in Period

• Prior and concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

7.3 Start of Treatment Period: Visit 1, Dose 1 (Day 0)

• Eligibility review (Section 6.2)
• Randomization to treatment (Section 6.13)
• Urine pregnancy test (females) (Section 6.8)
• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Complete physical examination (Section 6.6)
• 12-Lead ECG (Section 6.7)
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis (Section 6.8)
• PK baseline sample collection (Section 6.9)
• PD baseline sample collection (Section 6.10)
• Baseline anti-drug antibody sample collection (Section 6.11)
• Prior and concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)
• Quality of life assessments (Section 6.15)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.4 Site Contact with the Subject

• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

7.5 Continuation of Treatment Period: Visit 2, Dose 2 (Day days)

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.6 Continuation of Treatment Period: Visit 3, Dose 3 (Day days)

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Complete physical examination (Section 6.6)
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis (Section 6.8)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.7 Continuation of Treatment Period: Visit 4, Dose 4 (Day days)

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.8 Continuation of Treatment Period: Visit 5, Dose 5 (Day days)

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Complete physical examination (Section 6.6)
• 12-Lead ECG (Section 6.7)
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis (Section 6.8)
• PK sample collection (Section 6.9)
• PD sample collection (Section 6.10)
• Anti-drug antibody sample collection (Section 6.11)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose. This 2 hour assessment of vitals may be dismissed if, based on the discretion of the Investigator and the absence of safety signals, the Investigator determines that the subject only needs to be monitored for 1 hour post dose. The post-dose monitoring period may be lengthened back to 2 hours at any time by the Sponsor based on SSC recommendation.
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.9 Continuation of Treatment Period: Visits 6 and 7, Doses 6 and 7 (Days 70 and 84, all days)

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose. This 2 hour assessment of vitals may be dismissed if, based on the discretion of the Investigator and the absence of safety signals, the Investigator determines that the subject only needs to be monitored for 1 hour post dose. The post-dose monitoring
  period may be lengthened back to 2 hours at any time by the Sponsor based on SSC recommendation.
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.10 Continuation of Treatment Period: Visit 8, Dose 8 (Day days)

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Complete physical examination (Section 6.6)
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis (Section 6.8)
• Pregnancy test, serum or urine (females) (Section 6.8)
• PK sample collection (Section 6.9)
• PD sample collection (Section 6.10)
• Anti-drug antibody sample collection (Section 6.11)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)
• Quality of life assessments (Section 6.15)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose. This 2 hour assessment of vitals may be dismissed if, based on the discretion of the Investigator and the absence of safety signals, the Investigator determines that the subject only needs to be monitored for 1 hour post dose. The post-dose monitoring period may be lengthened back to 2 hours at any time by the Sponsor based on SSC recommendation.
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.11 Continuation of Treatment Period: Visits 9 and 10, Doses 9 and 10 (Days 112 and 126, all days)

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose. This 2 hour assessment of vitals may be dismissed if, based on the discretion of the Investigator and the absence of safety signals, the Investigator determines that the subject only needs to be monitored for 1 hour post dose. The post-dose monitoring period may be lengthened back to 2 hours at any time by the Sponsor based on SSC recommendation.
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.12 Continuation of Treatment Period: Visit 11, Dose 11 (Day days)

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Complete physical examination (Section 6.6)
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis (Section 6.8)
• PK sample collection (Section 6.9)
• PD sample collection (Section 6.10)
• Anti-drug antibody sample collection (Section 6.11)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose. This 2 hour assessment of vitals may be dismissed if, based on the discretion of the Investigator and the absence of safety signals, the Investigator determines that the subject only needs to be monitored for 1 hour post dose. The post-dose monitoring period may be lengthened back to 2 hours at any time by the Sponsor based on SSC recommendation.
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.13 Continuation of Treatment Period (Day day)

• 12-Lead ECG (Section 6.7)

7.14 Continuation of Treatment Period: Visits 12 and 13, Doses 12 and 13 (Days 154 and 168, all ± 3 days)

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

• Administer IMP (Section 6.14)

• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 and 2 hours post-dose. This 2 hour assessment of vitals may be dismissed if, based on the discretion of the Investigator and the absence of safety signals, the Investigator determines that the subject only needs to be monitored for 1 hour post dose. The post-dose monitoring period may be lengthened back to 2 hours at any time by the Sponsor based on SSC recommendation.
• Concomitant therapy (Section 6.12)
• AE collection (Section 6.16)

7.15 Completion of Treatment Period: Visit 14, Day days

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Complete physical examination (Section 6.6)
• 12-Lead ECG (Section 6.7)
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis (Section 6.8)
• Urine pregnancy test (females) (Section 6.8)
• PK sample collection (Section 6.9)
• PD sample collection (Section 6.10)
• Anti-drug antibody sample collection (Section 6.11)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)
• Quality of life assessments (Section 6.15)
• Discharge from study:
• Subjects will be offered the option of enrolling in the DX-2930-04 Open Label Extension (OLE) study for continued treatment and safety follow-up.
• Informed Consent obtained for study DX-2930-04
• Subjects who consent to participate in DX-2930-04 will receive their first OLE dose following the completion of all double-blind assessments scheduled on Day 182.

7.16 Follow-up Period (Subjects Not Continuing in Open-Label Extension Study): Visit 15, Day days

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• PK sample collection (Section 6.9)
• PD sample collection (Section 6.10)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)

7.17 Final Follow-up Visit (Subjects Not Continuing in Open-Label Extension Study): Visit 16, Day days

• Vital signs including body temperature, HR, BP and RR (Section 6.5)
• Complete physical examination (Section 6.6)
• 12-Lead ECG (Section 6.7)
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis (Section 6.8)
• Urine pregnancy test (females) (Section 6.8)
• PK sample collection (Section 6.9)
• PD sample collection (Section 6.10)
• Anti-drug antibody sample collection (Section 6.11)
• Concomitant therapy (Section 6.12)
• HAE attack information (Section 6.4)
• AE collection (Section 6.16)
• Quality of life assessments (Section 6.15)

7.18 Early Termination (ET)

8 QUALITY CONTROL AND ASSURANCE

9 DATA ANALYSIS / STATISTICAL METHODS

9.1 Sample Size Determination

9.2 Analysis Populations

9.3 Analysis of Disposition

9.4 Demographics and Baseline Characteristics Analyses

9.5 Analysis of Pharmacokinetic and Pharmacodynamic Endpoints

9.5.1 Pharmacokinetic Assessments:

9.5.2 Pharmacodynamic Assessments:

9.5.3 Immunogenicity Assessments:

9.5.4 C1-INH and C4 Assessments:

9.6 Analysis of Primary and Secondary Efficacy Endpoints

PROC GENMOD DATA = XXXX ;
WHERE x<=visitn<=y;
    CLASS Trta (REF = 'Placebo') usubjid;
    MODEL attack=trta priordx base/ DIST=poisson;
    REPEATED SUBJECT=usubjid / CORR=ind;
    LSMEANS trta/DIFF CL ILINK;
    ODS OUTPUT diffs - meandiff lsmeans = means;
RUN;

9.7 Safety Analysis

9.8 Analysis of Quality of Life Assessments

10 STUDY ADMINISTRATIVE STRUCTURE

Table 2. Study Administrative Structure

Sponsor Contact:	Ryan Iarrobino PPD , Clinical Development 55 Network Drive, Burlington, MA 01803 Phone: PPD Email: PPD
Sponsor Medical Director:	PPD , MD PPD , Medical Research 55 Network Drive, Burlington, MA 01803 Phone: PPD Email: PPD
Medical Monitor (US, Canada):	PPD, MD Rho, Inc. PPD ,PPD ,PPD Phone: PPD Email: PPD
Medical Monitor (Jordan, Europe)	PPD ,M.D. Voisin Consulting Phone: PPD Email: PPD
Study Monitoring (US):	Rho, Inc. PPD ,PPD ,PPD Phone: PPD
Study Monitoring (Jordan)	Triumpharma PPD PPD , PPD PPD Phone: PPD , PRD
Study Monitoring (Canada)	Red Maple Trials Incorporated Phone: PPD
Study Monitoring (Europe)	Dyax Corp 55 Network Drive, Burlington, MA 01803 Phone: PPD

10.1 Institutional Review Board/Research Ethics Board/Independent Ethics Committee

10.2 Ethical Conduct of the Study

10.3 Subject Information and Consent

10.4 Subject Confidentiality

10.5 Study Monitoring

10.6 Case Report Forms and Study Records

10.7 Study Safety Committee

10.8 Protocol Violations/Deviations

10.9 Access to Source Documentation and On-Site Audits

10.10 Data Generation and Analysis

10.11 Retention of Data

10.12 Financial Disclosure

10.13 Publication and Disclosure Policy

11 REFERENCE LIST

12 APPENDICES

Appendix 1 Study Activities Schedule

Appendix 2 National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (Modified) (US National Institutes of Health; National Institute of Allergy and Infectious Diseases)

Appendix 3 National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Tables (Modified) (US National Institutes of Health; National Institute of Allergy and Infectious Diseases)

Appendix 4 HAE Attack Assessment and Reporting Procedures (HAARP)