A Proof-of-Concept Study of AC-201 to Prevent Gout Flares

• Sponsor: TWi Biotechnology, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01712204
• Collaborator: (none)
• Enrollment: 82
• Location: 1
• Arms: 2
• Duration (Months): 8
• Patients Per Site Per Month: 10.3

Study Details

Study Description

Brief Summary

Initiation of ULT for gout increases the occurrence of acute gouty arthritis flares due to mobilization of urate from tissue deposits. IL-1β plays a key role in mediating the inflammatory response in gouty arthritis. The efficacy of IL-1β blockade in the prophylaxis of gouty flares during initiation of ULT has been validated in multiple trials of IL-1β inhibitor therapies. Therefore, it is believed that IL-1β is a relevant therapeutic target for gout flares. AC-201 is an IL-1β modulator indicated for the treatment of osteoarthritis with good safety record and very few contraindications to the co-morbidities commonly among gout patients. AC-201 has also been demonstrated to have uric acid-lowering effects in clinical trials. The favorable product profile of AC-201 overall provides a strong rationale for investigating its clinical utility as prophylaxis against flares when initiating ULT.

Condition or Disease	Intervention/Treatment	Phase
Gout Flares	Drug: Placebo; Drug: AC-201; Drug: Febuxostat	Phase 2

Detailed Description

Clinical trials have demonstrated that anti-IL-1 agents (IL-1Ra, IL-1 Trap, and anti-IL-1β monoclonal antibody) can reduce the frequency of gout flares during the initial period of treatment with urate-lowering therapy and prevent of gout flares in gout patients with frequent flares. AC-201 is an oral IL-1 modulator but with a mechanism distinct from that of existing anti-IL-1 agents. The active metabolite of AC-201 has been shown in vitro and in vivo to inhibit the production and activity of IL-1, down-regulate IL-1 receptors, and increase IL1-Ra. Molecular research further suggests that these effects are mediated upstream via inhibition of MAPK signaling pathways and binding of NF-κB and AP-1 transcription factors that encode for a range of pro-inflammatory factors, including IL-1β, TNF-α, IL-6, IL-8, iNOS, and MMPs, which have been implicated in gout flares. AC-201 has also been demonstrated to have uric acid-lowering effects in clinical trials. The favorable product profile of AC-201 overall provides a strong rationale for investigating its clinical utility as prophylaxis against flares when initiating ULT.

Study Design

• Study Type: Interventional
• Actual Enrollment: 82 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Trial Of AC-201 In Subjects With Gout Initiating Urate-Lowering Therapy
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo plus Febuxostat	Drug: Placebo; Placebo Capsule BID for 16 Weeks; Other Names: PBO ; Drug: Febuxostat; Febuxostat 80 mg QD for 16 Weeks; Other Names: ULT
Experimental: AC-201 AC-201 plus Febuxostat	Drug: AC-201; AC-201 50mg Capsule BID for 16 Weeks; Drug: Febuxostat; Febuxostat 80 mg QD for 16 Weeks; Other Names: ULT

Outcome Measures

Primary Outcome Measures

1. Number of Gout Flares Per Subject [16 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female age 20 to 80 years, inclusive

• Meets at least 6 of the 12 American College of Rheumatology preliminary criteria (1977) for the classification of acute arthritis of primary gout, OR have proven tophus or documented monosodium urate (MSU) crystals in the joint fluid

• Serum uric acid ≥7.5 mg/dL at screening

• Experienced ≥2 gouty arthritis flares within one year prior to screening

Exclusion Criteria:

• Occurrence of a gouty arthritis flare ongoing at screening or during the screening period through baseline

• Use of allopurinol, febuxostat, benzbromarone, probenecid, or sulfinpyrazone within 4 weeks prior to screening

• Use of colchicine, glucocorticoids, NSAIDs, or COX-2 inhibitors within 1 week prior to screening

• Other (non-gout) chronic arthritis, acute inflammatory arthritis, autoimmune diseases with arthritis, or any condition requiring chronic daily use of pain medication

• History of allergy to any components of study medication, including diacerein

• Allergy, contraindication, or intolerance to febuxostat

• Contraindication or allergy to NSAIDs

• Severe renal impairment

• Any prior use of biologic anti-inflammatory therapy, such as IL-1 modulators, tumor necrosis factor inhibitors, IL-6 inhibitors, or T-cell costimulation modulator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Veterans General Hospital	Taipei		Taiwan

Sponsors and Collaborators

• TWi Biotechnology, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: TWi Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT01712204
• Other Study ID Numbers: AC-201-GOU-001
• First Posted: Oct 23, 2012
• Last Update Posted: May 22, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by TWi Biotechnology, Inc.: Prophylaxis of Acute Gout Flares; Urate-Lowering Therapy; Hyperuricemia; Gouty arthritis
• Additional relevant MeSH terms: Gout; Febuxostat

Study Results

Participant Flow

Recruitment Details	Overall, 82 patients from 8 clinical centers participated in the study between 28 January 2013 to 04 September 2013.
Pre-assignment Detail	Participants were assessed at an initial screening visit within 2 weeks before the baseline visit.

Arm/Group Title	Placebo	AC-201
Arm/Group Description	Placebo Capsule BID for 16 Weeks	AC-201 50mg Capsule BID for 16 Weeks
Period Title: Overall Study
STARTED	41	41
COMPLETED	33	36
NOT COMPLETED	8	5

Baseline Characteristics

Arm/Group Title	Placebo Capsule BID	AC-201 50mg Capsule BID	Total
Arm/Group Description	Placebo Capsule BID for 16 Weeks	AC-201 50mg Capsule BID for 16 Weeks	Total of all reporting groups
Overall Participants	41	41	82
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.6 (11.8)	43.7 (12.6)	43.6 (12.1)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	41 100%	41 100%	82 100%

Outcome Measures

1. Primary Outcome

Title	Number of Gout Flares Per Subject
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	AC-201
Arm/Group Description	Placebo Capsule BID for 16 Weeks Background therapy: Urate-Lowering Therapy (Febuxostat 80 mg QD)	AC-201 50mg Capsule BID for 16 Weeks Background therapy: Urate-Lowering Therapy (Febuxostat 80 mg QD)
Measure Participants	41	41
Least Squares Mean (95% Confidence Interval) [flares]	3.02	2.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, AC-201
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1356
	Comments
	Method	Possion regression
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.113
	Estimation Comments

Adverse Events

Time Frame	16 weeks
Arm/Group Title	Placebo		AC-201
Arm/Group Description	Placebo Capsule BID for 16 Weeks Background therapy: Urate-Lowering Therapy (Febuxostat 80 mg QD)		AC-201 50mg Capsule BID for 16 Weeks Background therapy: Urate-Lowering Therapy (Febuxostat 80 mg QD)
All Cause Mortality
	Placebo		AC-201
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		AC-201
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/41 (2.4%)		0/41 (0%)
Metabolism and nutrition disorders
Frequent Gout Attack	1/41 (2.4%)	1	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		AC-201
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/41 (26.8%)		10/41 (24.4%)
Blood and lymphatic system disorders
Anemia	0/41 (0%)	0	2/41 (4.9%)	2
Hepatobiliary disorders
Hepatic function abnormal	3/41 (7.3%)	3	2/41 (4.9%)	2
Infections and infestations
Nasopharyngitis	0/41 (0%)	0	2/41 (4.9%)	2
Investigations
Blood CPK increased	4/41 (9.8%)	4	1/41 (2.4%)	1
ALT increased	3/41 (7.3%)	3	0/41 (0%)	0
Creatinine renal clearance decreased	0/41 (0%)	0	2/41 (4.9%)	2
Musculoskeletal and connective tissue disorders
Tendonitis	1/41 (2.4%)	1	2/41 (4.9%)	2
Renal and urinary disorders
Renal Impairment	1/41 (2.4%)	1	2/41 (4.9%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.