Efficacy and Safety of Tradipitant in Diabetic and Idiopathic Gastroparesis: A Randomized, Placebo-Controlled Study

AbstractBackground and AimsThere is a high unmet need for the treatment of gastroparesis and studies of NK1-R antagonists suggest potential benefit in reducing the symptoms of nausea and vomiting. We hypothesized that tradipitant, an NK1-R antagonist, would be effective in treating patients with idiopathic or diabetic gastroparesis.MethodsIn a randomized, double-blind, placebo-controlled study across 47 U.S. sites, 152 gastroparesis patients were randomized to receive oral 85mg BID tradipitant (n=77) or placebo (n=75) daily for four weeks. Symptoms were assessed using a daily symptom dairy, Gastroparesis Cardinal Symptom Index (GCSI), and other patient reported questionnaires.ResultsPatients receiving tradipitant had a significant decrease in nausea score at Week 4 compared to placebo (−1.2 improvement vs −0.7, respectively, p=0.0099), and a significant increase in nausea-free days (28.8% increase on tradipitant vs 15.0% on placebo p=0.0160). Patients with both nausea and vomiting at baseline (n=101) showed an even greater decrease in nausea score (−1.4 improvement on tradipitant vs −0.4 on placebo p<0.0001) and an increase in nausea free days (32.3% improvement on tradipitant vs 7.6% on placebo p=0.0003). 32.9% of patients treated with tradipitant were nausea responders (average nausea score ≤ 1 at week 4) compared to 11.8% of patients on placebo (p=0.0013). 46.6% of patients treated with tradipitant had a greater than 1-point improvement in GCSI score compared to 23.5% of patients on placebo (p=0.0053).ConclusionsTradipitant treatment resulted in statistically and clinically meaningful improvements in nausea and overall gastroparesis symptoms. These robust efficacy results suggest tradipitant has the potential to become a useful pharmacological treatment for gastroparesis.

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P210 Efficacy and safety of filgotinib for patients with RA with inadequate response to methotrexate: FINCH1 primary outcome results

Rheumatology ◽

10.1093/rheumatology/keaa111.205 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

David Walker ◽

Bernard G Combe ◽

Alan J Kivitiz ◽

Yoshiya Tanaka ◽

Désirée van der Heijde ◽

...

Keyword(s):

Repeated Measures ◽

Study Drug ◽

Janus Kinase ◽

Controlled Study ◽

Stock Ownership ◽

Inadequate Response ◽

Efficacy And Safety ◽

Double Blind ◽

Mixed Effect ◽

Patient Reported

Abstract Background Filgotinib (FIL) is an oral, potent, selective Janus kinase 1 inhibitor that has shown good efficacy and was well tolerated for treatment of rheumatoid arthritis (RA). The objective of this study was to evaluate efficacy and safety of FIL treatment in patients with RA who have had an inadequate response to methotrexate (MTX). Methods This Phase 3, double-blind, active- and placebo (PBO)-controlled study randomised patients with active RA (3:3:2:3) to FIL 200mg, FIL 100mg, adalimumab [ADA] 40mg every 2 weeks, or PBO daily for up to 52 weeks; results through week 24 are presented. Patients also received background MTX. Primary efficacy endpoint was proportion of patients achieving ACR20 at week 12; additional clinical assessments included ACR50 and ACR70 and DAS28-CRP score ≤3.2 and <2.6, and patient-reported outcomes including HAQ-DI. Safety endpoints included adverse event types and rates. Logistic regression was used for superiority test of FIL vs PBO for ACR response and other binary endpoints, while mixed-effect model for repeated measures (MMRM) were used for continuous endpoints. Non-inferiority test of FIL to ADA (preserving >50% of ADA response) was performed for DAS28-CRP ≤3.2 and <2.6. Results Of 1,759 patients randomised, 1,755 received study drug: 475 FIL 200mg; 480 FIL 100mg; 325 ADA; and 475 PBO, of which 89.5%, 90.4%, 88.9%, and 81.3%, respectively, completed 24 weeks of study drug. 81.8% were female, mean (standard deviation [SD]) duration of RA was 7.8 (7.6) years, and mean (SD) DAS28-CRP was 5.7 (0.9). At week 12, significantly more patients in the FIL 200mg and 100mg arms achieved an ACR20 improvement vs PBO (Table 1). More patients receiving FIL achieved ACR50 and ACR70 improvements, DAS28-CRP scores ≤3.2 and <2.6 and reported improvements in HAQ-DI scores versus PBO (Table 1). Non-inferiority of FIL 200mg to ADA was met based on DAS28-CRP ≤3.2. The FIL safety profile was consistent with prior studies through Week 24. Conclusion FIL 200mg and 100mg led to significant improvement in signs and symptoms of RA, prevented radiographic progression, improved physical function compared to PBO, and was well-tolerated. Efficacy of FIL 200mg was non-inferior to ADA based on DAS28-CRP ≤3.2. Disclosures D. Walker: Other; Received support from Lilly, Pfizer, Novartis and Roche. B.G. Combe: Honoraria; Received honoraria from AbbVie, BMS, Gilead, Janssen, Eli Lilly and Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB. A.J. Kivitiz: Consultancies; Consultant to AbbVie, Celgene, Horizon, Jansses, Merck, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, SUN Pharma Advanced Research, Boehringer Ingelheim, Flexion and Novartis. Shareholder/stock ownership; Shareholder of Novartis. Y. Tanaka: Honoraria; Honoraria from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly ans Co., Pfizer, AbbVie, YL Biologics, BMS, Takeda, Misubishi-Tanabe, Novartis, Eisai, Janssen, Teijin. Grants/research support; Grant support from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, BMS, UCB, Daiichi-Sankyo, Eisai, Ono, Astellas, Eli Lilly, Pfizer, Abbvi and YL. D. van der Heijde: Corporate appointments; Director of Imaging Rheumatology bv. Consultancies; Consultant for consultant for AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. L. Ye: Corporate appointments; Employee of Gilead Sciences, Inc.. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. N. Mozaffarian: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. R.B.M. Landewé: Consultancies; Consultant for AbbVie, AstraZeneca, BMS, Galapagos, Pfizer, Eli Lilly, Novartis, and UCB.. S. Bae: None. E.C. Keystone: Consultancies; Consultant for AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer,, PuraPharm, Sandoz, Sanofi-Aventis, Sanofi-Genzyme, Samsumg Bioepsis, and UCB. P. Nash: Consultancies; Consultant for AbbVie, BMS, Jansses, Pfizer, Roche, Lilly, Sanofi, MSD, Novartis, Celgene and Gilead.

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Topical Application of Apremilast in the Treatment of Mild to Moderate Psoriasis

New Medical Innovations and Research ◽

10.31579/jnmir/006 ◽

2021 ◽

Vol 2 (1) ◽

pp. 01-10

Author(s):

Srikanth Kalakoti

Keyword(s):

Side Effects ◽

Treatment Options ◽

Unmet Need ◽

Autoimmune Disorder ◽

Controlled Study ◽

Efficacy And Safety ◽

Double Blind ◽

Average Percentage ◽

Topical Dosage ◽

Topical Gels

Background: Psoriasis is a chronic, autoimmune disorder that affects the skin and joints with an approximate global prevalence of 2–3%. Mild to moderate psoriasis is highly prevalent in about 80% of the global psoriatic population (2-3%). Currently available treatment options for mild to moderate psoriasis are topical dosage forms. Though a variety of topical formulations available, they are associated with different side effects. There is an unmet need for a product that can be used for a prolonged period with minimal side effects. Hence, Apremilast gel was developed and clinical proof of concept study (POC) was performed to investigate the efficacy and safety in mild to moderate psoriasis patients. Methods: A single-center randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of apremilast topical gels 2% & 4% w/w, in adult mild to moderate psoriatic patients for 12 weeks. Patients were examined at weeks 0, 2, 4, 8, and 12 weeks to assess the efficacy and safety. At 0 and 8 weeks, blood samples were collected to investigate the pharmacokinetics. The significance in % recovery was calculated statistically. Results: Both gels exhibited a significant reduction in PASI values when compared with baseline PASI scores. The average percentage inhibition of PASI with test products i.e. 2% and 4% w/w Apremilast topical gels is about 46.8% and 34.6% respectively after 12 weeks of treatment. Both the test products have not shown any adverse effects, hematological & biochemical changes and have exhibited Cmax less than 20ng/ml after 6 hours of application. Conclusion: Results have shown that topically applied apremilast could be an effective and safe option for the management of mild to moderate psoriasis.

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Eptinezumab for the prevention of chronic migraine: efficacy and safety through 24 weeks of treatment in the phase 3 PROMISE-2 (Prevention of migraine via intravenous ALD403 safety and efficacy–2) study

The Journal of Headache and Pain ◽

10.1186/s10194-020-01186-3 ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Stephen Silberstein ◽

Merle Diamond ◽

Nada A. Hindiyeh ◽

David M. Biondi ◽

Roger Cady ◽

...

Keyword(s):

Chronic Migraine ◽

Patient Reported Outcomes ◽

Controlled Study ◽

Efficacy And Safety ◽

Phase 3 ◽

Double Blind ◽

Patient Global Impression ◽

Calcitonin Gene ◽

Patient Reported ◽

Global Impression Of Change

Abstract Background PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of repeat intravenous (IV) doses of the calcitonin gene-related peptide–targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with chronic migraine. This report describes the results of PROMISE-2 through 24 weeks of treatment. Methods Patients received up to two 30-min IV administrations of eptinezumab 100 mg, 300 mg, or placebo separated by 12 weeks. Patients recorded migraine and headache endpoints in a daily eDiary. Additional assessments, including patient-reported outcomes, were performed at regularly scheduled clinic visits throughout the 32-week study period (screening, day 0, and weeks 2, 4, 8, 12, 16, 20, 24, and 32). Results A total of 1072 adults received treatment: eptinezumab 100 mg, n = 356; eptinezumab 300 mg, n = 350; placebo, n = 366. The reduction in mean monthly migraine days observed during the first dosing interval (100 mg, − 7.7 days; 300 mg, − 8.2 days; placebo, − 5.6 days) was further decreased after an additional dose (100 mg, − 8.2 days; 300 mg, − 8.8 days; placebo, − 6.2 days), with both doses of eptinezumab demonstrating consistently greater reductions from baseline compared to placebo. The ≥50% and ≥ 75% migraine responder rates (MRRs) increased after a second dose, with more eptinezumab-treated patients experiencing migraine response than placebo patients (≥50% MRRs weeks 13–24: 100 mg, 61.0%; 300 mg, 64.0%; placebo, 44.0%; and ≥ 75% MRRs weeks 13–24: 100 mg, 39.3%; 300 mg, 43.1%; placebo, 23.8%). The percentages of patients who improved on patient-reported outcomes, including the Headache Impact Test and Patient Global Impression of Change, increased following the second dose administration at week 12, and were greater with eptinezumab than with placebo at all time points. No new safety concerns were identified with the second dose regarding the incidence, nature, and severity of treatment-emergent adverse events. Conclusion Eptinezumab 100 mg or 300 mg administered IV at day 0 and repeated at week 12 provided sustained migraine preventive benefit over a full 24 weeks and demonstrated an acceptable safety profile in patients with chronic migraine. Trial registration ClinicalTrials.gov (Identifier: NCT02974153). Registered November 23, 2016.

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A randomized double-blind controlled study on the efficacy and safety of Sangdantongluo granule in the treatment of post-stroke spasticity

10.21203/rs.3.rs-679035/v1 ◽

2021 ◽

Author(s):

le xie ◽

Yao Xie ◽

Guo Mao ◽

Junlin Jiang ◽

Ting Yao ◽

...

Keyword(s):

Secondary Outcome ◽

Controlled Study ◽

Efficacy And Safety ◽

Double Blind ◽

Post Stroke ◽

Modified Ashworth Scale ◽

The Common ◽

To Receive ◽

Primary Measure ◽

Ashworth Scale

Abstract BackgroundStroke is the first leading cause of mortality and disability worldwide, and post-stroke spasticity (PSS) is the common complication of stroke. Sangdantongluo Granule, a modern patent Traditional Chinese medicine (TCM), is widely used in clinical practice to treat PSS. Whereas, there is limited evidence of effectiveness for Sangdantongluo Granule to treat PSS. This study will evaluate the clinical efficacy and safety of Sangdantongluo granule in the treatment of PSS. MethodsThis multicenter, randomized, double-blind and placebo-controlled study will recruit 132 participants in China who develops PSS 15 days to 90 days after stroke. Participants will be randomly assigned in an equal ratio to receive either Sangdantongluo granule or placebo for 2 months twice a day orally. The primary measure is the Modified Ashworth Scale (MAS), Secondary outcome measures include Compopsite Spasticity Scale (CSS), Simplified Fugl-Meyer Motor Scale (S-FM), National Institute of Health stroke scale (NIHSS), Modified Rankin Scale (mRS), Modified Barther Index (MBI), and Surface electromyography. Adverse events will be supervised throughout the trial. DiscussionThe results of this study will present whether Sangdantongluo granule is clinical effective and safe for managing PSS.Trial registrationClinicalTrials.gov ChiCTR2100044544. Registered on 23 March 2021.

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P217 Efficacy and safety of filgotinib for patients with RA naïve to MTX therapy: FINCH3 primary outcome results

Rheumatology ◽

10.1093/rheumatology/keaa111.212 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

Neil McKay ◽

Désirée van der Heijde ◽

Rene Westhovens ◽

William F. C Rigby ◽

Daniel W. T Ching ◽

...

Keyword(s):

Study Drug ◽

Signs And Symptoms ◽

Janus Kinase ◽

Controlled Study ◽

Stock Ownership ◽

Efficacy And Safety ◽

Double Blind ◽

Acr20 Response ◽

Patient Reported ◽

Oral Steroids

Abstract Background Filgotinib (FIL), an orally administered, potent, selective inhibitor of janus kinase 1 (JAK1), has shown good efficacy and was well tolerated for treatment of rheumatoid arthritis (RA). The objectives of this study were to compare efficacy and safety of FIL with and without methotrexate (MTX) in patients with RA who were naïve to MTX therapy. Methods This Phase 3, double-blind, active-controlled study randomised patients with moderately to severely active RA (2:1:1:2) to FIL 200mg daily+MTX, FIL 100mg+MTX, FIL 200mg (+placebo [PBO]), or MTX (+PBO) up to 52 weeks; results are through week 24. Primary endpoint was proportion achieving ACR20 response at week 24. Safety endpoints included adverse events types and rates. Results Of 1,252 randomised patients, 1,249 received study drug (416 FIL 200mg+MTX; 207 FIL 100mg+MTX; 210 FIL 200mg monotherapy; 416 MTX monotherapy) and were analysed; 1,130 completed week 24. Most (76.9%) were female; mean time since RA diagnosis was 2.2 years (median 0.4 years); mean (standard deviation [SD]) DAS28-CRP was 5.7 (1.0); and 35.9% were using oral steroids at baseline. At week 24, significantly more patients in the FIL 200mg+MTX (81.0%; P<0.001) and FIL 100mg+MTX (80.2%; P<0.05) arms achieved an ACR20 response compared to MTX monotherapy (71.4%)(Table 1). Compared to MTX monotherapy, more patients receiving FIL with or without MTX achieved ACR50 and ACR70 responses, DAS28-CRP <2.6 and ≤3.2, and reported improvements in SF-36 PCS (Table 1). The onset of activity was rapid, with significantly more patients achieving ACR50 and DAS28-CRP <2.6 with FIL than MTX at week 2. The FIL safety profile was consistent with prior studies through week 24. Serious AEs were observed in 4.1%, 2.4%, 4.8%, and 2.9% of patients in the FIL 200mg+MTX, FIL 100mg+MTX, FIL 200mg monotherapy, and MTX monotherapy groups, respectively. There was 1 death from lupus cardiomyopathy. Conclusion The JAK1 inhibitor FIL in combination with MTX led to significant improvements in RA signs and symptoms, physical function, and patient-reported outcomes compared to MTX alone and was well tolerated in patients with early active RA naïve to MTX. Clinically meaningful response to FIL occurred as early as 2 weeks after treatment initiation. Disclosures N. McKay: None. D. van der Heijde: Corporate appointments; Director of Imaging Rheumatology bv. Consultancies; Consultant for AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda Pharmaceutical Company Ltd., UCB. R. Westhovens: Corporate appointments; Advisor for Celltrion and Galapagos/Gilead. Other; Advisor for Celltrion and Galapagos/Gilead. W.F.C. Rigby: Consultancies; Consultant for Gilead. D.W.T. Ching: Corporate appointments; Speaker for AbbVie. Member of speakers’ bureau; Speaker for AbbVie. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Z. Yin: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. N. Mozaffarian: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. O.D. Messina: Honoraria; Received Honoraria from Pfizer, Amgen, and Americas Health Foundation (AHF). R.B.M. Landewé: Consultancies; Consultant for AbbVie, AstraZeneca, BMS, Galapagos, Pfizer, Eli Lilly, Novartis, and UCB. T. Atsumi: None. G.R. Burmester: Honoraria; Received Honoraria from AbbVie, Gilead, Eli Lilly, and Pfizer.

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Prevention of Relapse in Reflux Esophagitis: A Placebo Controlled Study of Ranitidine 150 mg BID and 300 mg BID

Canadian Journal of Gastroenterology ◽

10.1155/1997/954342 ◽

1997 ◽

Vol 11 (1) ◽

pp. 83-88 ◽

Cited By ~ 4

Author(s):

John H Hegarty ◽

Lars Halvorsen ◽

Bouke P Hazenberg ◽

Andrzej Nowak ◽

Colin L Smith ◽

...

Keyword(s):

Reflux Esophagitis ◽

Controlled Study ◽

Efficacy And Safety ◽

Double Blind ◽

Parallel Group ◽

Symptomatic Relapse ◽

To Receive ◽

Prevention Of Relapse ◽

Relapse Rates

OBJECTIVE:To compare the efficacy and safety of long term use of ranitidine 150 mg bid, 300 mg bid and placebo in prevention of endoscopic and symptomatic relapse of reflux esophagitis in an international, double-blind, placebo controlled, parallel group study.PATIENTS AND METHODS:A total of 279 patients at least 18 years old from hospital out-patient departments with healed esophagitis (grade 0) with no or mild symptoms entered the study. Patients were randomly allocated to receive ranitidine 150 mg, 300 mg or placebo twice daily for 48 weeks. Patients returned for symptom assessments at eight-week intervals and for re-endoscopy every 16 weeks.RESULTS:Both ranitidine regimens were significantly more effective than placebo in preventing endoscopic and symptomatic relapse of reflux esophagitis (P=0.003 for ranitidine 150 mg bid; P<0.001 for ranitidine 300 mg bid). No statistically significant differences were observed in relapse rates between the two ranitidine regimens. The percentage of patients with endoscopic relapse (grade 2) after 48 weeks were 60%, 37% and 27% for placebo, ranitidine 150 mg bid and ranitidine 300 mg bid, respectively (P=0.002 for ranitidine 150 mg bid versus placebo; P<0.001 for ranitidine 300 mg bid versus placebo). Ranitidine was well tolerated.CONCLUSIONS:Ranitidine 150 mg bid and 300 mg bid are safe and effective treatments in the prevention of reflux esophagitis relapse.

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EPIK-P2: A prospective phase 2, double-blind, randomized, placebo-controlled study of alpelisib in pediatric and adult patients (Pts) with PIK3CA-related overgrowth spectrum (PROS).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps3160 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS3160-TPS3160

Author(s):

Guillaume Canaud ◽

Juan Carlos López Gutiérrez ◽

Adrienne M. Hammill ◽

Lisa Weibel ◽

Ghislaine Vincent ◽

...

Keyword(s):

Pik3ca Mutation ◽

Disease Onset ◽

Unmet Need ◽

Controlled Study ◽

Anatomical Site ◽

Phase 2 ◽

Double Blind ◽

Α Subunit ◽

Patient Reported ◽

Prospective Phase

TPS3160 Background: Somatic gain-of-function mutations in the PIK3CA gene, encoding the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic α subunit (p110α), can result in PI3K pathway hyperactivation. PROS is an umbrella term for rare, phenotypically varied, but overlapping features driven by PIK3CA mutations. Disease onset is often congenital or in early childhood; presentation ranges widely from localized overgrowth to pleiotropic, severe overgrowth. Complications depend on anatomical site and extent of overgrowth. Management of PROS currently involves symptomatic treatment of its manifestations; an unmet need exists for targeted, systemic therapies. Alpelisib, a PI3Kα inhibitor, has demonstrated encouraging clinical observations and a promising safety profile; after 6 mo of treatment, pediatric and adult pts with PROS experienced improvements in symptoms without requiring surgery. A low rate of side effects was observed (Venot Q, et al. Nature. 2018;558:540-6). Methods: EPIK-P2 is a prospective, phase 2, multicenter study with an upfront 16-week, randomized, double-blind, placebo-controlled period. Key eligibility criteria include male or female ≥6 yr of age with PROS and symptomatic and/or progressive overgrowth; ≥1 PROS-related measurable lesion confirmed by a Blinded Independent Review Committee (BIRC) and documented somatic PIK3CA mutation. Pts with isolated cases of macrodactyly, epidermal nevus/nevi, or macrocephaly in absence of other PROS-related lesions; previous treatment with PI3K inhibitor(s); or debulking surgery within 3 mo are not eligible. Approximately 138 pts will be enrolled into 2 groups comprising adult (age ≥18 yr) and pediatric (ages 6-17 yr) pts. Pts will be randomized 2:1 to daily oral alpelisib or matching placebo; adults will receive 125 mg and pediatric pts 50 mg. After 16 weeks, pts randomized to placebo will switch to alpelisib in a blinded fashion; pts receiving alpelisib will continue alpelisib. Treatment will continue for up to 5 yr. The primary objective is to demonstrate the efficacy of alpelisib by the proportion of pts randomized to alpelisib with a response at Week 24 in each group. Response is defined as ≥20% volume reduction in the symptomatic target lesion(s) per BIRC. The key secondary objective is to demonstrate efficacy of alpelisib vs placebo based on the proportion of pts in each group with response at Week 16. Other secondary outcomes include safety and tolerability, duration of response, overall clinical response rates, changes in symptoms and comorbidities, patient-reported outcomes, pharmacokinetics, and healthcare utilization. An exploratory group of pts (n = 12) ages 2-5 yr will be later enrolled once a starting dose of alpelisib is confirmed in these pts. Enrollment of 150 pts is anticipated. Clinical trial information: NCT04589650.

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