Designing a Phase 3 trial with AI

March 28, 2024

We wanted to see if AI could help design a clinical trial. We asked AI to help design a Phase 3 in chronic spontaneous urticaria. The below output is what the tool generated.

Disease Overview

Chronic Spontaneous Urticaria (CSU) is a condition characterized by the spontaneous appearance of wheals (hives), angioedema, or both for more than six weeks without an obvious external trigger. The wheals are usually itchy and can cause significant discomfort and impact on quality of life. Angioedema is a deeper form of swelling that can occur with or without wheals and often affects the face, hands, feet, and genitalia.

CSU is an immune disorder that involves mast cell activation and is often linked to autoimmunity in many cases. The precise cause of CSU remains unknown, but it is thought to involve a combination of genetic, environmental, and immunological factors. The disease is more common in adults, particularly in middle-aged women, although it can occur at any age.

Description of the Disease

• Immune disorder involving mast cell activation
• Often linked to autoimmunity
• Unknown precise cause
• Common in adults, especially middle-aged women

Diagnosis

• Primarily clinical, based on history and physical examination
• Diagnostic tests may include complete blood count, erythrocyte sedimentation rate, C-reactive protein level, and tests for thyroid function and autoantibodies

Symptoms

• Red, raised, itchy welts on the skin
• Welts may vary in size and shape, appearing anywhere on the body
• Angioedema or swelling in deeper layers of the skin

Prognosis

• Course can be unpredictable
• Symptoms may resolve spontaneously within a year or two, but can persist for many years for others
• Significant impact on quality of life

Standard of Care

• First-line treatment involves second-generation H1 antihistamines
• High-dose antihistamines as a next step if symptoms are not adequately controlled
• Second-line or third-line options may include leukotriene receptor antagonists, omalizumab, and cyclosporine

Unmet Need

• Significant proportion of patients have symptoms not adequately controlled by current treatments
• Need for new therapeutic options that are effective, safe, and long-term
• Better understanding of disease mechanisms to guide development of targeted therapies

Research into the underlying mechanisms of CSU, novel treatment targets, and the development of new therapeutic agents is ongoing to address these unmet needs and improve the management of patients with this challenging condition.

Relevant approved drugs

The Phase 3 studies supporting the FDA's approval of Omalizumab for chronic idiopathic urticaria (CIU) are:

• Study 4577 (Preliminary dose-ranging trial):

  • Patient age: 12 to 75 years
  • Patient characteristics: Symptomatic on H1 antihistamines
  • Treatment groups: Xolair 75 mg (23 patients), Xolair 300 mg (25 patients), Xolair 600 mg (21 patients), Placebo (21 patients)
  • Primary efficacy variable: UAS7 score change from baseline at week 4
  • Regions and Year: US, Germany [2009-2010]

• Study 4881 (Pivotal efficacy and safety Study 1):

  • Patient age: 12 to 75 years
  • Patient characteristics: Symptomatic on H1 antihistamines
  • Treatment groups: Xolair 75 mg (77 patients), Xolair 150 mg (80 patients), Xolair 300 mg (81 patients), Placebo (80 patients)
  • Primary efficacy variable: Change from baseline to week 12 in weekly itch severity score
  • Regions and Year: US, Western and Eastern Europe, Turkey [2011-2012]

• Study 4882 (Pivotal efficacy and safety Study 2):

  • Patient age: 12 to 75 years
  • Patient characteristics: Symptomatic on H1 antihistamines
  • Treatment groups: Xolair 75 mg (82 patients), Xolair 150 mg (82 patients), Xolair 300 mg (79 patients), Placebo (79 patients)
  • Primary efficacy variable: Change from baseline to week 12 in weekly itch severity score
  • Regions and Year: US, Western and Eastern Europe, Turkey [2011-2012]

• Study 4883 (Study assessing symptoms in patients on high doses of antihistamines):

  • Patient age: 12 to 75 years
  • Patient characteristics: Symptomatic and on high doses of antihistamines
  • Treatment groups: Xolair 300 mg (252 patients), Placebo (83 patients)
  • Primary efficacy variable: Change from baseline to week 12 in weekly itch severity score
  • Regions and Year: US, Western and Eastern Europe, Australia, New Zealand, Singapore [2011-2012]

These studies provided the clinical data supporting the efficacy and safety of Omalizumab (Xolair) for the treatment of CIU at the recommended doses of 150 mg and 300 mg administered every 4 weeks.

Phase 3 Study Name	Number of Patients Enrolled	Primary Endpoint	Timepoint When Primary Endpoint Was Measured	Status
Study 4577	90	UAS7 score change from baseline	Week 4	Completed
Study 4881	318	Change from baseline to week 12 in weekly itch severity score	Week 12	Completed
Study 4882	323	Change from baseline to week 12 in weekly itch severity score	Week 12	Completed
Study 4883	335	Change from baseline to week 12 in weekly itch severity score	Week 12	Completed

The FDA's summary review does not explicitly mention whether the sponsor had to complete any open-label extension or additional safety studies before the approval of Omalizumab (marketed as Xolair) for chronic idiopathic urticaria (CIU). However, the summary notes that the safety profile of Xolair in patients with asthma had already been established, and the safety data specifically for CIU came from the studies listed in the review (Studies 4577, 4881, 4882, and 4883). The safety findings from these studies did not raise any new safety concerns for Xolair in the treatment of CIU.

Regarding the patient exposure to Omalizumab across the relevant studies, we can calculate the number based on the information provided for each study:

• Study 4577: 69 patients received Omalizumab (23 at 75 mg, 25 at 300 mg, and 21 at 600 mg).
• Study 4881: 238 patients received Omalizumab (77 at 75 mg, 80 at 150 mg, and 81 at 300 mg).
• Study 4882: 243 patients received Omalizumab (82 at 75 mg, 82 at 150 mg, and 79 at 300 mg).
• Study 4883: 252 patients received Omalizumab (all at 300 mg).

This adds up to a total exposure across all the phase 3 trials of 802 patients who received Omalizumab at various dosages.

As for the duration of exposure, the review indicates the following:

• Study 4577 had a treatment duration wherein the primary endpoint was measured at week 4, suggesting that the exposure was at least for this period.
• Studies 4881 and 4882 had a primary endpoint measurement at week 12, indicating patients were exposed to the treatment for at least 12 weeks.
• Study 4883 is also described as having a primary endpoint measured at week 12, again indicating an exposure of at least 12 weeks.

Thus, patients across the phase 3 trials were exposed to Omalizumab for variable durations ranging from 4 weeks to at least 12 weeks. It should be noted, though, that these details provide the minimum exposure required to meet the primary endpoint, and the actual length of treatment could be longer, especially if follow-up periods were involved post-treatment. For specifics regarding the total duration of patient exposure throughout each trial including follow-up periods, more detailed information from the individual study reports would be needed.

Relevant Phase 3 trials

The below table summarizes the primary endpoints studied in relevant pivotal Phase 3 trials in CSU.

Primary endpoints

Nct Id	Sponsor	Title	Start date	Status	Primary endpoints
NCT04426890	Celltrion	To Compare Efficacy and Safety of CT-P39 and EU-approved Xolair in...	2020-12-09	COMPLETED	Change from baseline in ISS7 and relative potency
NCT02329223	Novartis Pharmaceuticals	Study of Efficacy and Safety of Omalizumab in Refractory Chronic Spontaneous	2014-12	COMPLETED	Change from baseline in weekly itch severity score
NCT05774639	Kashiv BioSciences, LLC	Study to Compare Efficacy Safety and Immunogenicity of ADL-018 With...	2023-08-15	RECRUITING	Change from baseline in ISS7 and relative potency
NCT03580369	Novartis Pharmaceuticals	A Phase III Study of Safety and Efficacy of Ligelizumab in the Treatment...	2018-10-17	COMPLETED	Mean change from baseline in UAS7
NCT05032157	Novartis Pharmaceuticals	A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment...	2021-12-01	COMPLETED	Change from baseline in UAS7, and ISS7 and HSS7 scores
NCT04180488	Sanofi	Dupilumab for the Treatment of Chronic Spontaneous Urticaria in Patients...	2019-12-11	RECRUITING	Change from baseline in weekly itch severity score
NCT06042478	Novartis Pharmaceuticals	A Phase 3b Study to Assess the Efficacy, Safety, and Tolerability of...	2023-11-15	RECRUITING	Change from baseline in UAS7
NCT03328897	Novartis Pharmaceuticals	Study of Efficacy and Safety of Xolair® (Omalizumab) in Chinese Patients...	2017-04-26	COMPLETED	Change from baseline in ISS7
NCT03580356	Novartis Pharmaceuticals	A Phase III Study of and Efficacy of Ligelizumab in the Treatment of CSU...	2018-10-20	COMPLETED	Mean change from baseline in UAS7
NCT05030311	Novartis Pharmaceuticals	A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment...	2021-11-30	COMPLETED	Change from baseline in UAS7, and ISS7 and HSS7 scores

The primary endpoints in the Phase 3 studies for Chronic Spontaneous Urticaria (CSU) include:

• Change from baseline in Urticaria Activity Score over 7 days (UAS7)
• Change from baseline in Weekly Itch Severity Score (ISS7)
• Change from baseline in Weekly Hives Severity Score (HSS7)

These endpoints are measures of the severity of urticaria (hives) and pruritus (itching), which are the two main symptoms of CSU. UAS7 is a composite score that includes both the number and severity of hives and the severity of itch over a week. ISS7 is focused on the severity of itch alone, and HSS7 is focused on the severity of hives, each over a 7-day period.

In the context of Phase 3 studies for Chronic Spontaneous Urticaria (CSU), the most common primary endpoints appear to be related to symptom severity, incorporating patient-reported outcomes that assess the impact of treatment on hives and itching. The clinical relevance of each primary endpoint can be described as follows:

• Change from baseline in Urticaria Activity Score over 7 days (UAS7): UAS7 is an aggregate score that measures the severity and number of hives, as well as the severity of itching, over the course of a week. Each component (hives and itching) is scored daily on a 0-3 scale with the week's scores totaled for a range between 0 to 42. A higher score indicates more severe disease activity, so a reduction in UAS7 from baseline reflects clinical improvement. UAS7 is a widely accepted measure for assessing the effectiveness of CSU treatments, as it provides a comprehensive overview of disease burden on patients.

• Change from baseline in Weekly Itch Severity Score (ISS7): ISS7 specifically measures the severity of itching over a seven-day period, typically using a 0-3 scale each day, summed to provide a weekly score ranging from 0 to 21. Itching is a particularly bothersome symptom for patients with CSU, affecting the quality of life, sleep, and daily activities. Thus, ISS7 is an important clinical endpoint as it directly assesses the impact of treatment on one of the most distressing symptoms of CSU.

• Change from baseline in Weekly Hives Severity Score (HSS7): Similar to ISS7, HSS7 assesses the severity and number of hives over a week. By focusing exclusively on hives, HSS7 allows clinicians and researchers to evaluate how well a treatment reduces the physical manifestations of CSU, which are visible skin lesions.

The choice of primary endpoints in CSU clinical trials is driven by their ability to provide a quantifiable measure of how a treatment can alleviate symptoms and improve the quality of life for patients. These endpoints are also vital for regulatory authorities to determine the efficacy of new drugs and decide on their approval for clinical use.

It is notable that these endpoints are patient-reported, emphasizing the shift in clinical research toward capturing patients' perspectives on their own health and the impact of treatments. The clinical relevance of these primary endpoints is ultimately tied to their validity, reliability, and sensitivity to change, making them well-recognized standards for assessing treatment benefits in CSU.

When designing a Phase 2 or 3 study for Chronic Spontaneous Urticaria (CSU), it is important to select endpoints that robustly capture the efficacy of the intervention, reflect meaningful clinical outcomes, and align with current regulatory expectations as well as the state of scientific understanding. Based on the information and the current scientific and clinical landscape, the following primary endpoint is recommended:

Change from baseline in Urticaria Activity Score over 7 days (UAS7):

• Clinical Relevance: UAS7 is a well-established, validated measure directly related to the symptoms experienced by patients with CSU, including the number and severity of hives and the severity of itch. A reduction in the UAS7 score from baseline signifies clinical improvement and is likely to correlate with a reduction in disease burden.

• Regulatory Track Record: UAS7 has been frequently used in pivotal trials for approved CSU therapies and is often favored by regulatory agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Its use would facilitate comparisons with existing data and support the regulatory approval process.

• Patient-Centered: This endpoint is patient-reported, aligning with a broader industry and regulatory shift towards patient-centric outcomes. It reflects the impact of the disease and the treatment on the patient's quality of life.

• Sensitivity to Change: The UAS7 is sensitive to changes in disease activity, allowing for the detection of both clinical improvement and deterioration, which is essential for demonstrating the efficacy of a proposed therapeutic intervention.

• Practicality: The score is easy to collect and interpret, facilitating patient compliance and ensuring the integrity of data collection.

For Phase 2 studies specifically, where the focus is on determining the efficacy and optimal dosing, the UAS7 provides enough sensitivity to discern differences between various dosing regimens and placebo. For Phase 3 trials, which aim to confirm the efficacy and safety discovered in the earlier phases of development in a larger patient population, UAS7 helps provide clear, clinically meaningful data that can be used to support marketing applications.

The use of additional secondary endpoints, such as the Quality of Life (QoL) questionnaires (e.g., Chronic Urticaria Quality of Life Questionnaire, CU-Q2oL), would provide further information on the impact of the treatment from the patient's perspective. Moreover, depending on the mechanism of action of the investigational drug, biomarker-based endpoints could also provide insights into the drug's effect on the underlying disease processes.

In conclusion, while UAS7 is recommended as the primary endpoint for robustness and regulatory acceptance, incorporating a comprehensive set of secondary endpoints would provide a more holistic understanding of the treatment's impact on CSU.

To inform the design of a potential Phase 3 in CSU, the below table outlines relevant Phase 3 studies including duration, size and arms.

NCT ID	Sponsor	Experimental arms	Active comparators	Start date	Enrollment	# sites	Duration (primary)	Duration (complete)	Is drug approved for CSU?
NCT04426890	Celltrion	CT-P39, CT-P39, CT-P39	EU-approved Xolair, EU-approved Xolair, EU-approved Xolair	2020-12-09	634	1	681	n/a	No
NCT02329223	Novartis Pharmaceuticals	Omalizumab, Omalizumab		2014-12	218	39	365	n/a	Yes
NCT05774639	Kashiv BioSciences, LLC	Omalizumab Injection, Omalizumab Injection, Omalizumab Injection, Omalizumab Injection, Xolair Prefilled Syringe, Omalizumab Injection, Omalizumab Injection, Xolair Prefilled Syringe	Xolair Prefilled Syringe, Xolair Prefilled Syringe, Xolair Prefilled Syringe, Xolair Prefilled Syringe	2023-08-15	600	5	n/a	504	No
NCT03580369	Novartis Pharmaceuticals	Ligelizumab, Ligelizumab	Omalizumab	2018-10-17	1072	161	n/a	1003	No
NCT05032157	Novartis Pharmaceuticals	LOU064 (blinded), LOU064 (open-label)		2021-12-01	456	122	n/a	736	No
NCT04180488	Sanofi	Dupilumab SAR231893, non sedating H1-antihistamine, Dupilumab SAR231893, non sedating H1-antihistamine, Dupilumab SAR231893, non sedating H1-antihistamine		2019-12-11	384	102	n/a	1556	No
NCT06042478	Novartis Pharmaceuticals	Remibrutinib	Omalizumab	2023-11-15	468	61	n/a	639	No
NCT03328897	Novartis Pharmaceuticals	Omalizumab, Omalizumab		2017-04-26	418	27	n/a	818	Yes
NCT03580356	Novartis Pharmaceuticals	Ligelizumab, Ligelizumab	Omalizumab	2018-10-20	1078	182	976	n/a	No
NCT05030311	Novartis Pharmaceuticals	LOU064 (blinded), LOU064 (open-label)		2021-11-30	470	115	757	n/a	No

In considering the number of patients required for a CSU trial, the below factors are important to consider:

Effect Size Considerations with UAS7

The expected difference in UAS7 scores between the new treatment and Omalizumab sets the stage for sample size calculations. A smaller effect size, which might still be clinically significant, would necessitate a larger sample to achieve statistical significance. Historical data on UAS7 variations with Omalizumab treatment can offer insights into what magnitude of change would be considered meaningful.

Accounting for Variability

UAS7's design inherently captures day-to-day variability in CSU symptoms. This variability means that the standard deviation within the study population could be significant. To adequately power the study to detect a difference in UAS7 scores, you might need to increase the sample size beyond what initial estimates suggest.

Statistical Power and Significance

Given UAS7 as the primary endpoint, aiming for a high statistical power (90% or above) might be particularly advantageous to accommodate the endpoint's variability. This could slightly increase the required sample size but would improve the reliability of the study outcomes.

Dropout Rates and UAS7

Dropouts can significantly impact the study's ability to detect a difference in UAS7 scores. Planning for an attrition rate informed by similar studies and adjusting the enrollment target upwards to account for potential data loss is crucial. Ensuring robust follow-up mechanisms to minimize dropouts is also key.

Regulatory and Market Considerations

Regulators might scrutinize the choice of UAS7 as the primary endpoint, given its direct relevance to patient experience and symptom management. Demonstrating a statistically and clinically significant improvement in UAS7 scores compared to Omalizumab could support a strong value proposition for the new treatment, influencing both study size and design considerations.

Practicality and Feasibility

The feasibility of enrolling a large number of participants and conducting the study across multiple centers becomes even more critical when using a sensitive and variable endpoint like UAS7. Logistics, patient recruitment strategies, and site selection must all be optimized to support the study’s goals.