1. Sharon C. Murray, PhD JSM 29 July 2019
Design of a Phase 3 Trial for an Acute Treatment of a Rare Disease with Episodic Attacks
Sharon C. Murray, PhD
JSM
29 July 2019
Thank you for coming to this last session of the day.
Today I am going to walk you through the design of a phase 3 trial for a rare disease. With a rare disease, trial design is complicated due to the small number of available patients. In this example, I will talk about some of the different aspects of the design and hopefully show how statistical thinking can improve the design of the trial.

2. What is Hereditary Angioedema (HAE)?
A rare and potentially life-threatening genetic condition that occurs in approximately 1 in 10,000 to 1 in 50,000 people.
HAE symptoms include swelling in various parts of the body such as the hands, feet, face, abdomen and airway.
Patients may experience abdominal pain, nausea, and vomiting caused by swelling in the intestinal wall.
Airway swelling is particularly dangerous, because it can be fatal.
Children have a 50% chance of inheriting HAE if one parent has the disease.
Currently available acute attack treatments are parenterally administered
I’d like to start by telling you a little bit about the disease… Hereditary Angioedema is also known as HAE…
After first bullet…. The population of Raleigh is somewhere in the neighborhood of 500,000 people. That means that we would expect anywhere between 10 and 50 people in Raleigh to have this disease. Patients generally see specialists in allergy and immunology who treat the disease. Not all allergists treat it.
Airway swelling bullet … prior to available treatments, about 30% of patients died from their disease.
BioCryst has an oral medication for HAE and I’m here today to talk to you about the design of the phase 3 trial for acute treatment.
Information from US HAE Association - (accessed 31 May 2019)
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3. ZENITH-1 Trial Design
Phase 2 Trial of BCX7353, an Oral Kallikrein Inhibitor, as an Acute Treatment for HAE Attacks
End of Study
Visit
Screening Treatment Follow-Up
Screening
Sequence 1: A, P, A
Sequence 2: P, A, A
Sequence 3: A, A, P
A- Active BCX7353; P- Placebo
Trial part
Dose level
Protocol-specified n
Part 1
750 mg 36
Part 2
500 mg 12
Part 3
250 mg
Total 60
Before I can talk about the design of the Phase 3 trial, I need to talk about the information that we have from the Phase 2 trial.
The drug works by…
Confidential

4. Patient Diary: VAS Score at Pre-Dose, 1, 2, 3, 4, 8, and 24hr
The diary also included questions about:
Location of attack symptoms
Global ratings of severity
Global ratings of improvement/worsening
Use of HAE standard of care attack medication
Whether the subject felt the worst of the attack was over
Whether the subject felt the attack had completely ended
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5. Dose-Response was Observed in VAS Scores, Use of HAE Standard of Care Medication, and Improvement in Symptoms
CFB* in VAS
Use of Rescue Rx¥
Symptoms¥
When making a decision to go to Phase 3, it’s important to see a dose response from the Phase 2 study.
This information helped us make the decision to go forward with one dose.
*Change from baseline in 3-Composite VAS at 4 hours post-dose (least-squares mean difference from placebo in mm, 95% CI)
¥Analyses were performed using a generalized logistic model including treatment, period and sequence as fixed effects, and subject within sequence as a random effect. HAE standard of care attack medication was assessed in the 24 hours post-dose.
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6. Planning the Phase 3 Trial
Considerations
Choice of endpoint
Dose selection
What other drugs are on the market for treatment of acute attacks and how does that affect the design?
Sample size for RARE diseases
Crossover vs. parallel trial design
Sample size re-estimation or group sequential design?
Regulatory considerations
Single Phase 3 trial (Orphan Drug Designation)
Long-term safety requirements
When planning for the phase 3 trial, one of the first considerations is the choice of endpoint. We did not pre-specify the primary endpoint in the Phase 2 trial.
Confidential