Establishing outcome measures in early knee osteoarthritis.

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Abstract

[Indexed for MEDLINE] 7. JAMA. 2025 Feb 17;333(13):1138-49. doi: 10.1001/jama.2024.27643. Online ahead of print. CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial. Writing Committee for the HEALEY ALS Platform Trial; Berry JD(1), Maragakis NJ(2), Macklin EA(1), Chibnik LB(1), Quintana M(3), Saville BR(3), Detry MA(3), Vestrucci M(3), Marion J(3), McGlothlin A(3), Stommel EW(4), Chase M(1), Pothier L(1), Harkey BA(1), Yu H(1), Sherman A(1), Shefner J(5), Hall M(5), Kittle G(5), Babu S(1), Andrews J(6), D'Agostino D(1), Tustison E(1), Scirocco E(1), Giacomelli E(1), Alameda G(7), Locatelli E(7)(8), Ho D(1), Quick A(9), Ajroud-Driss S(10), Katz J(11), Heitzman D(12), Appel SH(13), Shroff S(13), Felice KJ(14), Simmons Z(15), Miller T(16), Olney N(17), Weiss MD(18), Goutman SA(19), Fernandes JA Jr(20), Jawdat O(21), Owegi MA(22), Foster L(23), Vu T(24), Ilieva H(25), Newman DS(26), Arcila-Londono X(26), Jackson C(27), Ladha S(5), Heiman-Patterson T(28), Caress J(29), Swenson A(30), Peltier A(31), Lewis R(32), Fee D(33), Elliott M(34), Bedlack R(35), Kasarskis EJ(36), Elman L(37), Rosenfeld J(38), Walk D(39), McIlduff CE(40), Twydell P(41), Young E(42), Johnson K(43), Rezania K(44), Goyal NA(45), Cohen JA(4), Benatar M(46), Jones V(47), Glass J(48), Shah J(49), Beydoun SR(50), Wymer JP(51), Zilliox L(52), Nayar S(53), Pattee GL(54), Martinez-Thompson J(55), Rynders A(54), Evan J(54), Evan J(54), Hartford A(56), Sepassi M(56), Ho KS(56), Glanzman R(56), Greenberg B(56), Hotchkin MT(56), Paganoni S(1)(57), Cudkowicz ME(1); HEALEY ALS Platform Trial Study Group. Collaborators: Hayden D, Lai PY, Donahue RA, Chen HW, Wang J, Mathai N, Lopes G, McCaffrey A, Scalia J, Luppino S, Lagier-Tourenne C, Sadri-Vakili G, Kolb S, Heintzman S, Sufit R, Szymanski A, Jenkins L, Martin A, Simpson Greene E, Thonhoff JR, Liao B, Whitaker C, Clawson LL, Uchil A, Riley KM, Arneklev J, Grogan J, Su X, Mamarabadi M, Malcolm A, Bazan T, Rad N, Wang LH, Feldman EL, Piccione E, Thaisetthawatkul P, Farmakidis C, Jabari D, Statland J, Pasnoor M, Dimachkie M, Brown RH Jr, Ghasemi M, Houmani H, Douthwright C, Daniello K, Suresh N, Farias J, Chen IA, Pasinelli P, Steijlen K, Bhavaraju-Sanka R, Jacobsen B, Milliard J, Bowser R, Deboo A, Cartwright MS, Nance C, Gutmann L, Yasek J, Harms M, Burford M, Diaz F, Shrilla D, Rakocevic G, Jones S, Solorzano G, Li X, Mahuwala Z, Kumaraswamy VVM, Quinn C, Baer M, Borg D, Bhuvaneswaran K, Kaur J, Maiser S, Rutkove SB, Mundwiler A, Meyer JA, Rao P, Roos R, Habib AA, Mozaffar T, Korb MK, Mullen J, Robbins NM, Carberry N, Granit V, Govindarajan R, Fournier CN, Oskarsson B, Darki L, Rodriguez R, Chuguilin M, McNeely W, Diaz-Abad M, Jin PH, Chauhan C, Bobenhouse J, Staff NP, Hayat G, Arroyave L, Bailey A, Bailey J, Barlow V, Bulat A, Changkuon G, Cirino M, Deignan C, Deirmendjian E, De Mattos A, DiStefano S, Drake K, Estes M, Faulconer K, Figueroa-Szostek P, Garozzo T, Hasenoehrl MG, Henrique J, Henrique N, Hurwitz S, Igne C, Irwin L, Jentoft K, Jordan B, Katsovskiy I, Kharakozova O, Kolvek T, Korin A, La T, Li H, Nguyen J, Novak I, Ortiz R, Ostrow J, Pagliaro J, Palillo J, Patel P, Patterson J, Phan M, Popel N, Proueng S, Rosenthal J, Small C, Tarasenko N, Thomas M, Vigneswaran P, Wahab Y, Whitworth I, Wright S, Connolly M, De Santiago D, Felix A, Garrett K, Hamilton J, Khan K, Lovett M, Nelson L, Pabon M, Rede D, Bolger P, Fetouh A, Woodcook J, Kamp C, Kennedy J, McGarry A, Torti M. Author information: (1)Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston. (2)Johns Hopkins University, Baltimore, Maryland. (3)Berry Consultants, Austin, Texas. (4)Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire. (5)Barrow Neurological Institute, Phoenix, Arizona. (6)Columbia University Medical Center, New York, New York. (7)Holy Cross Hospital, Fort Lauderdale, Florida. (8)Nova Southeastern University, Fort Lauderdale, Florida. (9)Ohio State University, Columbus. (10)Northwestern University, Chicago, Illinois. (11)California Pacific Medical Center, San Francisco. (12)Texas Neurology, Dallas. (13)Houston Methodist Neurological Institute, Houston, Texas. (14)Hospital for Special Care, New Britain, Connecticut. (15)Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania. (16)Washington University in St Louis, St Louis, Missouri. (17)Providence ALS Clinic, Portland, Oregon. (18)University of Washington, Seattle. (19)University of Michigan, Ann Arbor. (20)University of Nebraska Medical Center, Omaha. (21)University of Kansas Medical Center, Kansas City. (22)University of Massachusetts, Worcester. (23)University of Colorado Anschutz, Denver. (24)University of South Florida, Morsani College of Medicine, Tampa. (25)Jefferson Weinberg ALS Center, Philadelphia, Pennsylvania. (26)Henry Ford Hospital, Detroit, Michigan. (27)University of Texas Health Science Center, San Antonio. (28)Temple University, Philadelphia, Pennsylvania. (29)Wake Forest University School of Medicine, Winston-Salem, North Carolina. (30)University of Iowa, Iowa City. (31)Vanderbilt University Medical Center, Nashville, Tennessee. (32)Cedars-Sinai Medical Center, Los Angeles, California. (33)Medical College of Wisconsin, Milwaukee. (34)University of Virginia, Charlottesville. (35)Duke University, Durham, North Carolina. (36)University of Kentucky, Lexington. (37)University of Pennsylvania, Philadelphia. (38)Loma Linda University School of Medicine, Loma Linda, California. (39)University of Minnesota Twin Cities ALS Research Consortium, Minneapolis. (40)Beth Israel Deaconess Medical Center, Boston, Massachusetts. (41)Spectrum Health Medical Group, Grand Rapids, Michigan. (42)SUNY Upstate, Syracuse, New York. (43)Ochsner Health System, Covington, Louisiana. (44)University of Chicago, Chicago, Illinois. (45)University of California, Irvine Medical Center, Irvine. (46)University of Miami, Miami, Florida. (47)University of Missouri, Columbia. (48)Emory University, Atlanta, Georgia. (49)Mayo Clinic Jacksonville, Jacksonville, Florida. (50)University of Southern California, Los Angeles. (51)University of Florida Gainesville. (52)University of Maryland School of Medicine, Baltimore. (53)Georgetown University, Washington, DC. (54)Neurology Associates, Lincoln, Nebraska. (55)Mayo Clinic, Rochester, Minnesota. (56)Clene Nanomedicine, North East, Maryland. (57)Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, Massachusetts. Comment on JAMA. 2025 Feb 17. doi: 10.1001/jama.2025.0100. IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production. OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression. DESIGN, SETTING, AND PARTICIPANTS: CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR