Designing a Phase 3 trial with AI

March 28, 2024

This analysis was written by AI. For other AI analyses of biotech startups and products, see our research page.

Disease Overview

Description of the Disease

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin condition characterized by the occurrence of painful, recurring abscesses, nodules, and scarring primarily in areas of the body where skin rubs together, such as the armpits, groin, buttocks, and under the breasts. The disease often starts after puberty and can persist for many years, profoundly impacting the quality of life. HS is believed to be caused by a combination of genetic, environmental, and immune system factors. It involves the occlusion of hair follicles and subsequent inflammation. Though it was originally thought to originate from sweat glands, current understanding points towards follicular occlusion as the primary event in the disease process. The lesions associated with HS can cause significant pain and discomfort.

Diagnosis

Diagnosis of HS is primarily clinical, based on the patient's history and the characteristic appearance of the lesions. Key diagnostic criteria include the presence of typical lesions (deep-seated nodules, abscesses, and sinus tracts) in typical locations, a chronic and relapsing course, and a positive family history in some cases. There is no specific laboratory test for HS, but tests may be conducted to rule out other conditions or to assess complications, such as infections.

Symptoms

• Painful and inflamed nodules that can progress to abscesses
• Formation of tunnels under the skin, known as sinus tracts
• Significant scarring and skin changes
• Discharge of pus from the lesions
• Odor, particularly from leaking lesions

Prognosis

The prognosis of HS can vary significantly among individuals. It is generally a progressive disease that may worsen without appropriate treatment. Flare-ups may be triggered by hormonal changes, stress, heat, or friction. Managing comorbidities such as obesity, metabolic syndrome, and smoking is crucial, as these can influence disease severity and treatment outcomes.

Standard of Care

The treatment of HS is tailored to the severity of the disease:

• Mild cases are often managed with topical therapies (e.g., clindamycin) and regular hygiene measures.
• Moderate cases may require systemic antibiotics (e.g., tetracycline, clindamycin combined with rifampin) or hormonal treatments (e.g., anti-androgens like spironolactone).
• Severe cases might necessitate biologic drugs (most commonly adalimumab), or surgery to remove affected skin.

Pain management and psychological support are also essential components of care due to the chronic and distressing nature of the disease.

Unmet Need

Despite existing treatments, there remains a significant unmet need in the management of HS. Many patients experience inadequate control of their symptoms, prolonged time to diagnosis (often due to misdiagnosis or lack of awareness), and a high burden of treatment side effects. Furthermore, there is a need for treatments that more effectively halt disease progression, minimize side effects, and improve quality of life. Research continues into the underlying mechanisms of the disease and potential new therapeutic targets.

Relevant approved drugs

PIONEER I and II Trial Design

The PIONEER I and II trials were phase 3, multicenter studies designed to assess the efficacy and safety of adalimumab in treating hidradenitis suppurativa. Both trials featured two double-blind, placebo-controlled periods:

• Period 1: Patients were randomized in a 1:1 ratio to receive either 40 mg of adalimumab weekly or a matching placebo for 12 weeks.
• Period 2: Patients were reassigned to receive adalimumab weekly or every other week, or to continue with placebo for an additional 24 weeks.

Patient Enrollment

• PIONEER I: 307 patients were enrolled.
• PIONEER II: 326 patients were enrolled.

Primary Endpoint

The primary endpoint for both studies was a clinical response defined as at least a 50% reduction from baseline in the abscess and inflammatory-nodule count, with no increase in abscess count or draining-fistula counts by week 12.

Key Secondary Endpoints

Secondary endpoints included improvements in lesion counts, pain, and disease severity

Key Results

Clinical Response Rates at Week 12:

• PIONEER I: Adalimumab group had a 41.8% response rate vs. 26.0% in the placebo group (P=0.003).
• PIONEER II: Adalimumab group had a 58.9% response rate vs. 27.6% in the placebo group (P<0.001).

Improvement in Secondary Outcomes:

Notable improvements in secondary outcomes were reported in PIONEER II, showing significant benefits in lesion counts, pain, and disease severity scores at week 12 for the adalimumab group compared to placebo.

Safety:

• Period 1: Similar rates of serious adverse events were noted among adalimumab and placebo groups in both studies (1.3% in PIONEER I and 1.8% vs. 3.7% in PIONEER II).
• Period 2: Serious adverse event rates were below 4.6% across all groups in both studies, with no significant differences between them.

Conclusions

Adalimumab administered weekly significantly improved clinical response rates compared to placebo at 12 weeks in both PIONEER I and II trials. The incidence of serious adverse events was comparable between the adalimumab and placebo groups, supporting the treatment's safety profile.

Other relevant Phase 3 studies

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

Primary endpoints

NCT Id	Sponsor	Title	Start date	Status	Primary endpoints
NCT04242446	UCB Biopharma SRL	A Study to Evaluate the Efficacy and Safety of Bimekizumab in Study Participants With Moderate to Severe Hidradenitis Suppurativa	2020-02-19, ACTUAL	COMPLETED	Hidradenitis Suppurativa Clinical Response (HiSCR)
NCT05620823	Incyte Corporation	A Study to Evaluate the Efficacy and Safety of Povorcitinib (INCB054707) in Participants With Moderate to Severe Hidradenitis Suppurativa	2022-12-19, ACTUAL	RECRUITING	Hidradenitis Suppurativa Clinical Response (HiSCR)
NCT03713619	Novartis Pharmaceuticals	This is a Study of Efficacy and Safety of Two Secukinumab Dose Regimens in Subjects With Moderate to Severe Hidradenitis Suppurativa (HS).	2019-01-31, ACTUAL	COMPLETED	Hidradenitis Suppurativa Clinical Response (HiSCR)
NCT05889182	AbbVie	A Study to Assess Change in Disease Activity and Adverse Events of Oral Upadacitinib in Adult and Adolescent Participants With Moderate to Severe Hidradenitis Suppurativa Who Have Failed Anti-TNF Therapy	2023-06-21, ACTUAL	RECRUITING	Hidradenitis Suppurativa Clinical Response (HiSCR)
NCT04242498	UCB Biopharma SRL	A Study to Evaluate the Efficacy and Safety of Bimekizumab in Study Participants With Moderate to Severe Hidradenitis Suppurativa	2020-03-02, ACTUAL	COMPLETED	Hidradenitis Suppurativa Clinical Response (HiSCR)
NCT03713632	Novartis Pharmaceuticals	Study of Efficacy and Safety of Two Secukinumab Dose Regimens in Subjects With Moderate to Severe Hidradenitis Suppurativa (HS)	2019-02-25, ACTUAL	COMPLETED	Hidradenitis Suppurativa Clinical Response (HiSCR)
NCT05620836	Incyte Corporation	A Study to Evaluate the Efficacy and Safety of Povorcitinib (INCB054707) in Participants With Moderate to Severe Hidradenitis Suppurativa (HS)	2023-02-22, ACTUAL	RECRUITING	Hidradenitis Suppurativa Clinical Response (HiSCR)
NCT05905783	ACELYRIN Inc.	Hidradenitis Suppurativa Study of Izokibep	2023-06-22, ACTUAL	ACTIVE_NOT_RECRUITING	Hidradenitis Suppurativa Clinical Response (HiSCR)
NCT05819398	Boehringer Ingelheim	Lunsayil 1: A Study to Test Whether Spesolimab Helps People With a Skin Disease Called Hidradenitis Suppurativa	2023-04-10, ACTUAL	RECRUITING	Percent Change from Baseline in Draining Fistula/Tunnel Count

In the clinical studies for Hidradenitis Suppurativa (HS), the most common primary endpoints are variations of the Hidradenitis Suppurativa Clinical Response (HiSCR).

The HiSCR endpoint is clinically relevant for several reasons:

• Quantification of Disease Activity: HiSCR provides a quantitative measure of disease activity by considering the number of abscesses and inflammatory nodules, which are two of the most characteristic and symptomatic lesions in HS.
• Measurement of Treatment Efficacy: Achieving HiSCR (whether 50% or 75% reduction) is indicative of the treatment's efficacy. A 50% or greater reduction in lesion count is substantial enough to suggest that the medication has a strong therapeutic effect, improving patient outcomes.
• Focus on Symptom Severity: HS is a chronic, painful, and recurrent condition. The clinical relevance of HiSCR lies in its ability to reflect a meaningful decrease in the severity of HS symptoms, such as pain, suppuration, and the formation of new lesions, translating into potential improvements in quality of life for patients.
• Standardized Endpoint for Comparability: HiSCR is widely used in clinical trials for HS, which allows for comparability across different studies evaluating the efficacy of various therapies. Standardization helps clinicians understand the body of evidence and compare the effectiveness of different treatments.
• Balancing Sensitivity and Specificity: By requiring both a significant reduction in abscesses and nodules and no increase in draining tunnels or new abscess formation, HiSCR balances sensitivity (detecting true positives) and specificity (not misattributing naturally fluctuating symptoms to treatment effect).
• Adaptation to Different Study Goals: The variable numeric target in HiSCR (e.g., 50% vs. 75%) allows studies to adapt the endpoint to different therapeutic goals or investigate varying degrees of treatment response, ranging from moderate improvement to more stringent criteria for what constitutes a significant response.

Lastly, one primary endpoint mentioned in the provided table differs from the HiSCR model: "Percent Change from Baseline in Draining Fistula/Tunnel Count." While not as commonly reported as HiSCR, it is still clinically significant because draining fistulas and tunnels are severe manifestations of HS that significantly affect a patient's quality of life. Tracking changes in the number of draining tunnels can offer insights into disease progression and response to treatment, particularly therapies aiming to reduce the chronic inflammation that leads to such complicated lesions.

Historically, most Phase 3 studies in HS have primarily used HiSCR50 as the endpoint. This threshold, indicating a 50% reduction in disease severity, has been a standard measure of substantial clinical improvement. However, recent Phase 2 studies have increasingly employed HiSCR75, a more stringent measure demonstrating a 75% reduction, as the primary endpoint. This shift in Phase 2 trials towards HiSCR75 reflects an evolving clinical understanding and aims to capture more pronounced treatment effects that are particularly relevant in a competitive therapeutic landscape.

Given the progressive adoption of HiSCR75 in Phase 2 studies and its potential to more clearly differentiate the efficacy of treatments, there is a strong rationale for considering the adoption of HiSCR75 in Phase 3 trials as well. Using HiSCR75 could potentially align more closely with recent scientific insights and patient expectations for more effective therapies.

• Increased Sensitivity: HiSCR75 may offer increased sensitivity in detecting clinically meaningful improvements, crucial for conditions as debilitating as HS.
• Standardization and Comparability: Standardizing on a more stringent endpoint like HiSCR75 across both Phase 2 and Phase 3 trials may facilitate a more straightforward comparison of efficacy across studies, enhancing the clinical relevance of the findings.
• Regulatory Considerations: Engagement with regulatory bodies such as the FDA or EMA is crucial when considering such a shift in primary endpoints. It ensures that the endpoint will be robust enough to support marketing authorization, based on a comprehensive understanding of its impact and the therapeutic benefits observed.

Recommendation for Primary Endpoint:

Hidradenitis Suppurativa Clinical Response (HiSCR) is still acknowledged as a relevant and important primary endpoint for assessing efficacy in clinical trials for HS. I would recommend considering HiSCR with some refinement based on the aims of the study:

• Inclusion of Drainage: With HiSCR, ensuring there is no increase in draining fistulas or tunnels is important, as it prevents worsening of these particularly debilitating and severe manifestations of HS.
• Added Patient-Reported Outcomes (PROs): Including PROs as primary or key secondary endpoints could enhance the clinical relevance of the trial outcome. PRO measures can capture patient-perceived changes in pain, quality of life, or the symptomatic burden of HS.
• Disease Severity and Staging Scores: Utilizing the Hidradenitis Suppurativa Severity Index (HSSI) or International Hidradenitis Suppurativa Severity Score System (IHS4) can provide a more comprehensive assessment of disease severity changes. These could be used in conjunction with HiSCR for a broader understanding of clinical response.
• Incorporation of Biomarkers: If available, incorporating biomarkers of inflammation or disease activity could provide objective data to support clinical findings, particularly for drugs with a well-understood mechanism of action that targets specific inflammatory pathways.
• Longitudinal Assessment: Considering an endpoint that incorporates sustained response over time, rather than a single time point, can be pertinent to evaluate the durability of the treatment effect.

Considerations for Phase 2 vs. Phase 3 Studies:

• In Phase 2 studies, HiSCR endpoints can be used to establish preliminary efficacy and dose-response relationships. Phase 2 studies might also explore a range of clinically relevant endpoints to identify the most sensitive and specific measures.
• In Phase 3 studies, primary endpoints should be more firmly established, typically based on Phase 2 outcomes and in consultation with regulatory bodies. They should be sensitive enough to detect clinically meaningful changes and robust enough to support regulatory approval.

Engagement with Regulatory Bodies:

Engage with regulatory bodies (e.g., FDA, EMA) early in the trial design process to ensure the selected primary endpoint will be acceptable to support a future marketing authorization application. Regulatory feedback can also guide modifications to the endpoint based on the most recent clinical and scientific insights and the current therapeutic landscape.

In summary, an updated implementation of HiSCR, potentially augmented with patient-reported outcomes and other relevant measures, would be a comprehensive and clinically relevant primary endpoint choice for a Phase 2 or 3 study in Hidradenitis Suppurativa.

Study duration and enrollment

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

NCT Id	Sponsor	Experimental arms	Active comparator arms	Start date	Enrollment count	Num sites	Actual primary enrollment	Actual enrollment rate (pts/week)	Other enrollment rate (pts/week)
NCT04242446	UCB Biopharma SRL	Bimekizumab, Bimekizumab, Bimekizumab		2020-02-19	505	88	666.0	5.3	-
NCT05620823	Incyte Corporation	Povorcitinib, Povorcitinib		2022-12-19	600	90	-	-	5.8
NCT03713619	Novartis Pharmaceuticals		Secukinumab, secukinumab	2019-01-31	545	111	862.0	4.4	-
NCT05889182	AbbVie	Upadacitinib, Upadacitinib, Upadacitinib, Upadacitinib		2023-06-21	1328	170	-	-	12.0
NCT04242498	UCB Biopharma SRL	Bimekizumab, Bimekizumab, Bimekizumab		2020-03-02	509	91	505.0	7.0	-
NCT03713632	Novartis Pharmaceuticals		Secukinumab, Secukinumab	2019-02-25	545	108	829.0	4.6	-
NCT05620836	Incyte Corporation	Povorcitinib, Povorcitinib		2023-02-22	600	102	-	-	6.3
NCT05905783	ACELYRIN Inc.	Izokibep		2023-06-22	189	98	-	-	2.2
NCT05819398	Boehringer Ingelheim	Spesolimab Formulation 1, Spesolimab Formulation 2		2023-04-10	200	149	-	-	3.3

Designing a Phase 3 clinical trial for Hidradenitis Suppurativa (HS), especially one that aims to evaluate HiSCR75 as the primary endpoint, requires careful consideration of several factors.

HiSCR75 denotes a 75% reduction in abscess and inflammatory nodule counts without an increase in draining tunnels or abscesses. Achieving such a high threshold for clinical improvement indicates a substantial therapeutic effect, which is more challenging to achieve than HiSCR50. Therefore, it is crucial to plan the trial size and parameters to maximize the likelihood of detecting a statistically significant and clinically meaningful effect if one exists.

Considerations for Sizing a Phase 3 Study:

Historical Data Review:

Review data from prior studies targeting HS, especially those assessing HiSCR endpoints, to understand trends in response rates and variability. For example, in the provided trials, it's noted that enrollment counts varied widely (ranging from 189 to 1328). Also, where actual primary enrollment is listed, it often exceeds the initial enrollment count, suggesting a buffer for potential dropouts or non-responders.

Endpoint Specificity:

HiSCR75 is a more stringent endpoint than HiSCR50, implying that fewer patients are likely to achieve this outcome. This consideration should lead to an increased sample size to detect a significant difference between treatment and control arms if one exists.

Statistical Power and Sample Size:

• Higher statistical power is desirable for Phase 3 trials to ensure that a true effect of the treatment can be detected. Typically, a power of 80% to 90% is targeted.
• Calculating the required sample size will depend on expected effect size (difference in response rate between treatment and placebo), the standard deviation of the response, and the chosen level of statistical significance (commonly set at alpha = 0.05).

Adjustments for Dropouts and Non-compliance:

A higher dropout rate might be anticipated given the trial duration and the chronic, painful nature of HS. This must be factored into the initial sample size calculation to ensure sufficient power at study completion.

Site and Participant Considerations:

• Number of sites: More sites can aid faster recruitment and wider geographic representation but can increase variability and management complexity.
• Recruitment rate: Based on the table, actual enrollment rates per week varied. Planning around realistic recruitment rates, which reflect prior studies, helps set feasible timelines and expectations.

Regulatory and Ethical Considerations:

• Consultations with regulatory bodies early in the planning phase are crucial to align the study design with regulatory requirements for new drug approvals.
• Ethical considerations, particularly around the use of placebos in a chronic, debilitating condition like HS, should be addressed, potentially supporting the use of active comparators where feasible.

Example Calculation:

Assuming a baseline HiSCR75 response rate of 20% in the control group and aiming for a 35% response in the treatment group, a sample size calculation with 80% power and a significance level of 0.05 might be conducted. Including an assumption of about 20% dropout based on prior studies, this would influence the final number needed per group.

Practical Example:

Given these assumptions and using standard statistical formulas or software for sample size calculation, one might find that approximately 300 patients per arm could be necessary. Adjusting for dropouts, this might suggest enrolling at least 360 patients per arm initially.

Estimated trial duration

To estimate the duration of a Phase 3 trial in Hidradenitis Suppurativa (HS) targeting the HiSCR75 endpoint, let’s use the sample size estimate from the previous discussion—360 patients per arm, adjusting for a 20% dropout rate to achieve approximately 300 evaluable patients per arm. This will give us an example for calculating recruitment timelines based on the enrollment rates provided in the table.

From the table, we notice that the enrollment rates vary quite a bit among different studies, ranging from around 2.2 to about 12 patients per week across different trials. Here’s what we know about some specific trials:

• One trial had an enrollment rate of 11.994839 pts/week.
• Another trial had a rate of 6.325301 pts/week.
• Yet another trial had a rate of 5.761317 pts/week.

For our calculations, let’s consider a range of enrollment rates based on this data:

• Low rate: 2.2 pts/week
• Average rate: 6.5 pts/week (approximating an average of the mentioned rates)
• High rate: 12 pts/week

We need to recruit 720 patients in total (360 per arm). The duration of recruitment can be calculated as the number of patients divided by the enrollment rate per week. Based on the calculations:

• Low enrollment rate (2.2 patients/week): It would take approximately 327 weeks, or about 6.3 years, to recruit 720 patients.
• Average enrollment rate (6.5 patients/week): It would take approximately 111 weeks, or about 2.1 years, to recruit 720 patients.
• High enrollment rate (12 patients/week): It would take approximately 60 weeks, or about 1.2 years, to recruit 720 patients.

These estimates indicate the recruitment phase duration depending on different enrollment rates observed in similar trials. After recruitment, additional time for follow-up must be considered, typically at least 6 to 12 months, to measure the HiSCR75 responses and any long-term effects or adverse events. The total duration of the trial will be the sum of the recruitment period and the follow-up period.

Phase 2 studies

NCT Id	Sponsor	Brief title	Start date	Status	Primary endpoints
NCT03248531	UCB Biopharma SRL	A Study to Test ... Moderate to Severe Hidradenitis Suppurativa.	2017-09-22	COMPLETED	HiSCR at Week 12
NCT04876391	Boehringer Ingelheim	A Study Investigating ... Who Completed a Previous Clinical Trial	2021-07-27	COMPLETED	TEAEs up to week 120
NCT05849922	Sanofi	A Study to Test ... Adults With Hidradenitis Suppurativa	2023-06-06	RECRUITING	HiSCR at Week 16
NCT03929835	TO Pharmaceuticals	Study to Investigate ... Treatment of Subjects With Hidradenitis Suppurativa	2020-09-01	WITHDRAWN	HS-PGA score improvement at week 8
NCT04856930	AnaptysBio, Inc.	A Study to Evaluate ... Treatment of Subjects With Hidradenitis Suppurativa	2021-07-07	COMPLETED	Change from Baseline in AN count at Week 16
NCT05020730	Phoenicis Therapeutics	Trial to Determine ... Activity of PTM-001 in Patients With Hidradenitis Suppurativa	2022-05-05	RECRUITING	Effect on IL-1β levels in biopsies
NCT03001622	InflaRx GmbH	Studying Complement ... With Moderate to Severe Hidradenitis Suppurativa	2016-12	COMPLETED	TEAEs and anti-drug antibodies detection
NCT06028230	Sanofi	A Phase 2 Study ... Adult Participants With Moderate to Severe Hidradenitis Suppurativa	2023-09-29	RECRUITING	Percent change in AN count from baseline at Week 16
NCT03628924	Janssen Research & Development, LLC	A Study to Evaluate ... of Guselkumab for the Treatment of Participants ... HS	2018-09-04	COMPLETED	HiSCR at Week 16
NCT05216224	Aclaris Therapeutics, Inc.	ATI-450 vs Placebo ... Moderate to Severe Hidradenitis Suppurativa (HS)	2021-12-29	COMPLETED	Change from Baseline in AN count at Week 12
NCT06046729	Eli Lilly and Company	A Study of ... Adult Participants With Moderate to Severe Hidradenitis Suppurativa	2023-10-23	RECRUITING	HiSCR at Week 16
NCT04430855	AbbVie	A Study of Oral ... With Moderate to Severe Hidradenitis Suppurativa	2020-07-14	COMPLETED	HiSCR at Week 12
NCT05093855	Staidson (Beijing) ... Co., Ltd	Efficacy and Safety ... Injection in Patients With Moderate to Severe HS	2021-08-18	COMPLETED	Change in IHS4 score at Week 8
NCT00918255	Abbott	Study of Adalimumab ... With Moderate to Severe Chronic Hidradenitis Suppurativa	2009-04	COMPLETED	Clinical Response at Week 16
NCT03487276	InflaRx GmbH	Efficacy and Safety ... IFX-1 in Patients With Moderate to Severe HS	2018-02-26	COMPLETED	HiSCR at Week 16
NCT03926169	AbbVie	A Global Study ... Placebo in Adult Participants With Moderate to Severe HS	2019-06-03	COMPLETED	HiSCR at Week 16
NCT02421172	Novartis Pharmaceuticals	Efficacy, Safety, ... Study of CJM112 in Hidradenitis Suppurativa Patients	2015-04-13	COMPLETED	Clinical Responder Rate at Week 16
NCT03852472	ChemoCentryx	Evaluation of Safety ... Avacopan in Subjects With Moderate to Severe HS	2018-12-21	COMPLETED	HiSCR at Week 12
NCT05322473	MoonLake Immunotherapeutics AG	Evaluation of ... for the Treatment of Patients With Active Moderate to Severe HS	2022-04-25	COMPLETED	HiSCR at Week 12
NCT04476043	Incyte Corporation	To Assess the Efficacy ... INCB054707 in Participants With Hidradenitis Suppurativa	2020-08-25	COMPLETED	Change from Baseline in AN Count at Week 16
NCT05139602	AbbVie	A Study to Assess Disease...	2021-12-28	RECRUITING	HiSCR; Number of Participants with AEs
NCT05635838	Incyte Corporation	Study to Evaluate of the Efficacy...	2022-12-07	COMPLETED	Change from baseline in AN count
NCT05348681	Aristea Therapeutics, Inc.	A Study to Evaluate RIST4721...	2022-07-18	TERMINATED	Incidence of TEAEs; Incidence of SAEs
NCT05103423	Staidson (Beijing) Biopharmaceuticals Co.	Safety and Efficacy Study...	2021-06-24	COMPLETED	Number of participants with treatment-related AEs; Pharmacokinetic parameters
NCT04493502	Eli Lilly and Company	A Study of LY3041658...	2020-08-26	COMPLETED	HiSCR
NCT04988308	Janssen Research & Development, LLC	A Study of Bermekimab...	2021-10-12	TERMINATED	HiSCR50
NCT04756336	Pharma Holdings AS	LTX-109 as Treatment...	2021-03-05	COMPLETED	Investigator assessed signs for local reactions; Patient reported symptoms for local reactions
NCT04019041	Janssen Research & Development, LLC	A Study to Evaluate...	2019-09-16	COMPLETED	HiSCR
NCT01838499	AstraZeneca	Assessment of the Safety...	2013-05	TERMINATED	Clinically Relevant Response in PGA
NCT06118099	Sanofi	Proof-of-concept Study Evaluating...	2023-11-01	RECRUITING	HiSCR50
NCT04092452	Pfizer	A Study to Evaluate...	2019-12-02	COMPLETED	HiSCR
NCT03569371	Incyte Corporation	A Study of the Safety...	2018-07-17	COMPLETED	Number of Participants With TEAEs
NCT03512275	Janssen Research & Development, LLC	A Study of Bermekimab...	2018-06-20	COMPLETED	Number of Participants With AEs
NCT03827798	Novartis Pharmaceuticals	Study of Efficacy and Safety...	2019-02-27	RECRUITING	sHiSCR
NCT05355805	ACELYRIN Inc.	Hidradenitis Suppurativa Phase 2b...	2022-05-05	COMPLETED	HiSCR75
NCT04762277	Boehringer Ingelheim	A Study to Test Whether Spesolimab...	2021-04-06	COMPLETED	Percent change from baseline in AN count
NCT03607487	Incyte Corporation	A Placebo-Controlled Study...	2018-10-15	COMPLETED	Number of Treatment-emergent AEs

In the context of clinical trials for Hidradenitis Suppurativa (HS), a chronic inflammatory skin condition characterized by painful nodules, abscesses, and tunnels, the most common primary endpoints usually revolve around measures of disease severity, safety, and patient quality of life. Here are some of the most common primary endpoints and their clinical relevance:

• Hidradenitis Suppurativa Clinical Response (HiSCR): This is a widely used endpoint in HS clinical trials. It involves measuring the reduction in the number of inflammatory nodules and abscesses without an increase in the number of draining fistulas. A reduction of at least 50% from baseline is often used (referred to as HiSCR50), and variations such as HiSCR75 indicate a 75% reduction. The HiSCR is a clinically relevant measure because it reflects a significant improvement in disease symptoms that is meaningful to patients.
• Treatment-Emergent Adverse Events (TEAEs): Safety assessments such as the occurrence of TEAEs are critical in all phases of clinical trials. They provide information on the safety and tolerability profile of a drug, which is essential for regulatory approval and clinical use. Adverse events include both serious and non-serious events, categorizing how frequently patients experience side effects from the treatment.
• HS Physician's Global Assessment (HS-PGA): This is a clinician-reported measure based on an overall assessment of a patient's disease severity. It typically involves a scale ranging from clear to very severe. Improvement in HS-PGA score from baseline indicates therapeutic benefit. This measure helps healthcare providers assess the overall impact of the treatment on disease activity.
• Change in Abscess and Inflammatory Nodule (AN) Count: This endpoint measures the exact change in lesion count from the start of the trial. A decrease in the count is a direct measure of treatment efficacy against the inflammatory components of HS.
• Change in International Hidradenitis Suppurativa Severity Score System (IHS4): The IHS4 is a scoring system that takes into account the number of nodules, abscesses, and draining tunnels, each weighted by their clinical severity. This scoring system helps to categorize patients into mild, moderate, or severe disease categories and quantifies changes in disease severity over time, providing a holistic view of treatment impact.
• Participant Reported Outcomes (PROs): These include patient-reported measures on pain, quality of life, and other symptoms that are not captured by objective clinical measures. These endpoints are increasingly recognized as important as they reflect the direct impact of the disease and its treatment on patients' lives.
• Biomarkers: Some studies measure the effect of treatment on specific biomarkers such as IL-1β levels in skin biopsies, which could provide insights into the treatment's mechanism of action and its potential anti-inflammatory effects.
• Pharmacokinetics parameters: These include measures like the area under the plasma concentration versus time curve (AUC), peak plasma concentration (Cmax), and half-life of the drug. These are critical for understanding drug absorption, distribution, metabolism, and excretion, which influence dosing regimens.

Clinical relevance comes from how these endpoints reflect the therapeutic benefit or harm to the patient and the disease's pathophysiology. For chronic diseases like HS, endpoints should ideally capture both the immediate impact on disease symptoms and the long-term effects on quality of life, disease progression, and safety.

Phase 2 study duration and enrollment

NCT Id	Sponsor	Experimental arms	Active comparator arms	Start date	Enrollment count	Num sites	Actual primary enrollment	Actual primary enrollment rate (pts / week)	Other primary enrollment rate (pts / week)
NCT03248531	UCB Biopharma SRL	Bimekizumab	Adalimumab	2017-09-22	90	31	343.0	1.836735	-
NCT04876391	Boehringer Ingelheim	Spesolimab	-	2021-07-27	45	21	164.0	1.920732	-
NCT05849922	Sanofi	SAR442970	-	2023-06-06	84	55	-	-	1.519380
NCT03929835	TO Pharmaceuticals	Cannabis oil	-	2020-09-01	0	1	-	-	0.000000
NCT04856930	AnaptysBio, Inc.	Imsidolimab, Imsidolimab	-	2021-07-07	149	34	261.0	3.996169	-
NCT05020730	Phoenicis Therapeutics	PTM-001	-	2022-05-05	50	3	-	-	0.712831
NCT03001622	InflaRx GmbH	-	-	2016-12	12	1	78.0	1.076923	-
NCT06028230	Sanofi	SAR444656 (KT-474)	-	2023-09-29	99	30	-	-	1.772379
NCT03628924	Janssen Research & Development, LLC	Guselkumab dose 1, Guselkumab dose 2, Placebo...	-	2018-09-04	184	45	514.0	2.505837	-
NCT05216224	Aclaris Therapeutics, Inc.	ATI-450, Placebo oral tablet	-	2021-12-29	95	20	275.0	2.418182	-
NCT06046729	Eli Lilly and Company	Eltrekibart, Eltrekibart, Eltrekibart	-	2023-10-23	350	69	-	-	4.570896
NCT04430855	AbbVie	Upadacitinib, Upadacitinib, Placebo	-	2020-07-14	68	26	198.0	2.404040	-
NCT05093855	Staidson (Beijing) Biopharmaceuticals Co., Ltd	BDB-001 Injection	-	2021-08-18	41	15	678.0	0.423304	-
NCT00918255	Abbott	adalimumab, adalimumab	-	2009-04	154	26	222.0	4.855856	-
NCT03487276	InflaRx GmbH	IFX-1, IFX-1, IFX-1, IFX-1	-	2018-02-26	179	41	343.0	3.653061	-
NCT03926169	AbbVie	Risankizumab, Risankizumab, Risankizumab, Pla...	-	2019-06-03	243	59	610.0	2.788525	-
NCT02421172	Novartis Pharmaceuticals	CJM112, CJM112, CJM112	-	2015-04-13	66	16	478.0	0.966527	-
NCT03852472	ChemoCentryx	Avacopan, Avacopan, Avacopan, Avacopan	-	2018-12-21	435	91	671.0	4.538003	-
NCT05322473	MoonLake Immunotherapeutics AG	Sonelokimab (M1095), Sonelokimab (M1095)	Adalimumab	2022-04-25	234	57	295.0	5.552542	-
NCT04476043	Incyte Corporation	INCB054707, INCB054707, INCB054707	-	2020-08-25	209	40	365.0	4.008219	-
NCT05139602	AbbVie	Lutikizumab, Lutikizumab, Lutikizumab, Lutikizumab	-	2021-12-28	200	54	-	-	1.017442
NCT05635838	Incyte Corporation	Ruxolitinib cream, Vehicle cream	-	2022-12-07	69	20	204.0	2.367647	-
NCT05348681	Aristea Therapeutics, Inc.	RIST4721	-	2022-07-18	25	12	141.0	1.241135	-
NCT05103423	Staidson (Beijing) Biopharmaceuticals Co., Ltd	BDB-001 Injection, Placebo, BDB-001 Injection...	-	2021-06-24	50	15	687.0	0.509461	-
NCT04493502	Eli Lilly and Company	LY3041658	-	2020-08-26	72	20	454.0	1.110132	-
NCT04988308	Janssen Research & Development, LLC	Bermekimab, Placebo, Bermekimab, Bermekimab, ...	Adalimumab, Placebo	2021-10-12	151	54	255.0	4.145098	-
NCT04756336	Pharma Holdings AS	LTX-109 gel, 3% w/w	-	2021-03-05	11	1	76.0	1.013158	-
NCT04019041	Janssen Research & Development, LLC	bermekimab, bermekimab, placebo	-	2019-09-16	153	33	162.0	6.611111	-
NCT01838499	AstraZeneca	MEDI8968	-	2013-05	224	27	434.0	3.612903	-
NCT06118099	Sanofi	Amlitelimab	-	2023-11-01	84	25	-	-	1.523316
NCT04092452	Pfizer	PF-06650833, PF-06700841, PF-06826647	-	2019-12-02	194	77	658.0	2.063830	-
NCT03569371	Incyte Corporation	INCB054707	-	2018-07-17	10	4	195.0	0.358974	-
NCT03512275	Janssen Research & Development, LLC	Bermekimab Monoclonal Antibody 400 mg, Bermek...	-	2018-06-20	42	1	194.0	1.515464	-
NCT03827798	Novartis Pharmaceuticals	CFZ533, LYS006, MAS825, VAY736	LOU064 25mg, LOU064 100mg	2019-02-27	245	44	-	-	0.864851
NCT05355805	ACELYRIN Inc.	Izokibep, Izokibep, Izokibep	-	2022-05-05	176	44	370.0	3.329730	-
NCT04762277	Boehringer Ingelheim	Spesolimab	-	2021-04-06	52	25	204.0	1.784314	-
NCT03607487	Incyte Corporation	INCB054707, Placebo, INCB054707, Placebo, INCB054707	-	2018-10-15	35	13	218.0	1.123853	-

To size a Phase 2 study for Hidradenitis Suppurativa (HS) using HiSCR75 as the endpoint, we must consider several key factors: the expected effect size of the treatment, variance within the population, dropout rates, and the power required to detect a statistically and clinically significant difference. HiSCR75 is a stringent endpoint that requires a 75% reduction in the inflammatory lesion count, potentially showing a more pronounced effect for effective treatments. Here's a step-by-step approach to determine the appropriate sample size:

• Expected Effect Size
  Based on previous studies, anti-inflammatory biologics have demonstrated varying degrees of effectiveness. For example, adalimumab showed about a 50% response rate for HiSCR50. Assuming an improvement for HiSCR75 might be lower, an estimated effect size might be around 30-40% for biologics that effectively target the inflammatory pathways involved in HS.
• Control Group Response
  The placebo or control group's response rate is also crucial. For HS, placebo responses can be relatively low, around 10-20% for HiSCR. For HiSCR75, this might be even lower, possibly under 10%.
• Calculation of Sample Size
  For a conservative estimation and ensuring adequate power to detect differences between treatment and control, we can use these assumptions:
  • Treatment group response: 40%
  • Control group response: 10%
  • Desired power: 80% (common for Phase 2 trials)
  • Significance level: 5%
  These parameters can be used in a sample size calculation formula or software that is designed for comparing two proportions.
• Adjust for Dropout
  HS studies often face moderate dropout rates due to the chronic and painful nature of the disease. Planning for a 10-20% dropout rate might be prudent.
• Sample Size Estimation Example
  Using a sample size calculator for comparing two proportions with the inputs specified, we might find that each group needs approximately 50-70 participants to detect the expected effect size with 80% power and a significance level of 5%. Considering a dropout rate of 15%, you might increase this number by approximately 15-20%.
• Total Sample Size
  Thus, you would aim for about 60-80 participants per group initially, rounding to account for dropout, which suggests a total of 120-160 participants might be adequate.
• Final Considerations
  These numbers are an initial estimate and should be refined with more detailed statistical input, considering the specifics of the drug mechanism, historical data from similar compounds, and consultation with a biostatistician. It's also critical to consider the patient population's heterogeneity, as HS severity and response to treatment can vary widely.

By carefully planning the study size as above, you ensure sufficient power to detect meaningful clinical effects, thereby enhancing the potential for success in Phase 2 trials.

With active comparator

When including an active comparator arm in the Phase 2 study for Hidradenitis Suppurativa (HS) with HiSCR75 as the endpoint, we must adjust our approach to account for comparing two active treatments. This impacts the sample size calculation by potentially increasing the required number of participants, given that the differences in response rates between two active treatments are likely to be smaller than between an active treatment and a placebo.

Revised Assumptions for Sample Size Calculation:

• Treatment Group Response: Assuming the new biologic might have an improved efficacy, expect a 40% response rate achieving HiSCR75.
• Active Comparator Group Response: Given existing treatments like adalimumab have shown good efficacy, assume a 30% response rate for the comparator achieving HiSCR75.
• Desired Power and Significance Level: Retain an 80% power and a 5% significance level to detect differences.

Steps to Calculate Sample Size:

• Determine Effect Size: The difference in response rates (10% in this example) is smaller than compared to a placebo, requiring a larger sample size to detect this difference.
• Adjust for Dropout: Anticipate a dropout rate of 15-20% due to the chronic nature of HS and the potential side effects of treatments.

Sample Size Estimation:

• Using the assumptions:
  • Difference in Proportions: 10%
  • Power: 80%
  • Significance Level: 5%
  With these inputs, a standard sample size calculator for comparing two proportions would suggest an increase in the required sample size. Initial calculations might suggest approximately 100-130 participants per group before adjusting for dropout.

Including Dropout:

• Adding a 15-20% buffer for dropout, the numbers might need to be increased to approximately 120-156 participants per group.

Total Sample Size:

• Considering these adjustments, you would aim for around 240-312 participants in total. This ensures both groups are adequately powered to detect a statistically significant difference in the efficacy measured by HiSCR75.

Practical Considerations:

• Recruitment Feasibility: Evaluate the feasibility of recruiting a larger sample, considering the prevalence and severity distribution of HS in potential study locations.
• Resource Allocation: Larger sample sizes require more resources and careful logistical planning, especially when involving multiple treatments.
• Statistical Consultation: Work closely with a biostatistician to refine these estimates based on more sophisticated statistical models, potentially including interim analyses to adjust the study design or sample size based on preliminary results.

By carefully planning and adjusting the study design to include an active comparator, the trial's relevance to current treatment paradigms increases, providing clearer insights into the comparative effectiveness of new treatments for HS.

Phase 2 duration

Let's calculate the duration of the Phase 2 study for Hidradenitis Suppurativa (HS) using HiSCR75 as the endpoint, where the trial includes an active comparator arm.

Parameters and Assumptions:

• Target Total Sample Size: 240-312 participants (to ensure both groups are adequately powered to detect a statistically significant difference)
• Enrollment Rates: We need to select an appropriate rate from similar studies in the table. From more relevant trials (similar conditions or biologics), let's look at:
  • NCT03248531 (UCB Biopharma SRL): 1.836735 patients/week
  • NCT03628924 (Janssen Research & Development, LLC): 2.505837 patients/week
  • NCT04476043 (Incyte Corporation): 4.008219 patients/week

Average Weekly Enrollment Rate Calculation:

Calculating an average of these more relevant rates:

Average Enrollment Rate = (1.836735 + 2.505837 + 4.008219) / 3 ≈ 2.783597 patients/week

Calculation of Time Required for Enrollment:

• Lower Bound of Sample Size (240 participants):

  Duration for 240 participants = 240 / 2.783597 ≈ 86.2 weeks

• Upper Bound of Sample Size (312 participants):

  Duration for 312 participants = 312 / 2.783597 ≈ 112.1 weeks

Total Study Duration Including Follow-up:

• Enrollment Duration: Approximately 86-112 weeks (1.65 to 2.15 years).
• Follow-up Period: Assuming an additional 3 months (12 weeks) to assess HiSCR75.
• Close-out Period: An additional 1 month (4 weeks).

Total Estimated Study Duration:

• Total Duration (Lower Bound): 1.65 years + 4 months = about 2 years
• Total Duration (Upper Bound): 2.15 years + 4 months = about 2.5 years

This estimation allows for planning and managing the clinical trial, assuming average enrollment rates similar to those observed in other relevant biologic treatment trials for dermatological conditions.

Potential for Phase 1 or Phase 1/2 proof of concept

For a Phase 1 or Phase 1/2 clinical trial in Hidradenitis Suppurativa (HS), the development of a set of endpoints and a targeted patient population is essential to assess the feasibility of the intervention and to provide evidence of clinical activity. Here are the suggested endpoints and patient population criteria:

Suggested Endpoints:

• Clinical Response Rate:
  • Lesion Count Reduction: Assess the number of inflammatory nodules, abscesses, and draining fistulas at baseline and at the end of the study period.
  • Pain Score Reduction: Utilize validated pain assessment tools (e.g., Visual Analog Scale) to quantify changes in pain levels due to HS lesions.
• Inflammatory Biomarkers:
  • Serum Cytokine Levels: Measurement of inflammatory cytokines such as TNF-α, IL-1β, and IL-17 could provide biochemical evidence of drug activity.
  • HS-specific Inflammatory Markers: If available, assay for HS-specific markers (e.g., levels of kallikreins or other proteases) in blood or lesional skin samples.
• Quality of Life (QoL) Assessments:
  • Dermatology Life Quality Index (DLQI) or Hidradenitis Suppurativa Quality of Life (HiSQOL) tool to document changes in the patient's quality of life, which can be significantly affected by HS.
• Safety and Tolerability:
  • Adverse Events Monitoring: Record and evaluate any adverse events or side effects reported during the trial.
  • Local and Systemic Tolerability: Specifically for topical or locally administered treatments, assess the reaction at the application site alongside any systemic reactions.

Suggested Patient Population:

• Inclusion Criteria:
  • Adults aged 18 and over with a clinical diagnosis of moderate to severe HS (typically Hurley stage II or III).
  • Patients who have an inadequate response to standard treatments, such as antibiotics or hormonal therapies.
  • Active disease at enrollment, defined as a minimum number of abscesses and inflammatory nodules.
• Exclusion Criteria:
  • Patients currently on systemic corticosteroids or biologics that could affect the baseline inflammatory status (washout period required).
  • Those with concurrent infections or other skin conditions that could interfere with HS assessment.
  • Patients with significant comorbid conditions that might confound treatment outcomes or pose increased risk.

Study Design Considerations:

• Duration: The study should be long enough to allow observation of initial efficacy and safety, typically 8-12 weeks for initial phase studies.
• Sample Size: Due to the variability in response and the complexity of HS, a statistically justified sample size should be determined to detect meaningful clinical changes.
• Ethical Considerations: Given the chronic, painful, and often disabling nature of HS, the ethical rationale for early testing in affected patients is strong, particularly when current treatments are insufficient.