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1. A Randomized, Double-blind, Placebo-Controlled Study of Latrepirdine in Patients With Mild to Moderate Huntington Disease

Author

Kieburtz, K, Landwehrmeyer, GB, Cudkowicz, M, Dorsey, ER, Feigin, A, Hunt, V, Kayson, E, McDermott, M, Noonberg, S, Seitz, W, Soliveri, P, Walker, F, Burgunder, J-M, Romero, I, Magara, A, Stebler, Y, Rickards, H, Wright, J, De Souza, J, Barker, RA, Mason, S, Di Pietro, A, Goodman, A, O'Keeffe, D, Langlois, M, Ferland, G, Verret, L, Chouinard, S, Paris, S, LePage, C, Nemeth, AH, Merritt, C, Cox, C, Astbury, T, Murphy, S, Ahmed, A, St Marie, P, Berila, RA, Kubu, C, Segro, V, Kumar, R, Erickson, D, Schneiders, J, Frucht, S, Wasserman, P, Moskowitz, C, Scott, B, Perry-Trice, P, Wyne, S, Parida, D, Redaelli, V, Soltan, W, Robowski, P, Nowak, M, Schinwelski, M, Dziadkiewicz, A, Andrews, T, Ruddy, D, Dougherty, A, Boelmans, K, Schmalfeld, J, Muenchau, A, Zittel, S, Mallonee, W, Suter, G, Tan, J, Seeberger, L, Harris, J, Champion, J, Wojcieszek, J, Belden, J, Price, K, Hughes-Gay, M, Sprehn, G, Squitieri, F, Martino, T, De Gregorio, F, De Nicola, A, Elifani, F, Rosenblatt, A, Yoritomo, N, Margolis, R, Nichols, P, Palhagen, SE, Hoglund, AV, Paucar, M, Reza-Soltani, TW, Beister, A, Raab, T, Kieni, J, Schrenk, C, Banaszkiewicz, K, Misztela, J, Wojcik, M, Szczygiel, E, Golosz, M, Rudzinska, M, Roos, RAC, van den Bogaard, SJA, Bos, R, Booij, SJ, Hyson, C, Megens, J, Makaji, E, Jenkins, M, Hersch, S, Maya, S, Dresser, C, Rosas, D, Blindauer, K, Schindler, C, Hung, S, McNees, AA, Tabrizi, S, Novak, M, Say, M, Patel, A, Panegyres, P, Lewis, N, Jukich, S, Faull, C, Hjermind, LE, Jakobsen, O, Vogel, A, Nielsen, TR, Nielsen, JE, Kostyk, S, Seward, A, Agrawal, P, Kraakevik, J, Hogarth, P, Wilson, A, Lear, J, Kraus, PH, Saft, C, Steiner, T, Hoffmann, R, Stamm, C, Schollhammer, J, Uhl, I, Kaminski, B, O'Donovan, K, Quarrell, O, Nevitt, L, Kipps, C, Hare, A, Gunner, K, Hayward, E, Nance, M, Hamerlinck, J, Wielinski, C, Yastrubetskaya, O, Chiu, E, Chua, P, Mannaa, B, de Tommaso, M, Serpino, C, Cormio, C, Sciruicchio, V, De Michele, G, Di Maio, L, Russo, CV, Sacca, F, Salvatore, E, Tucci, T, Wolz, M, Klingelhoefer, L, Wolz, A, Schmidt, S, Storch, A, Spruth, E, Thiel, S, Neumann, B, Gelderblom, H, Priller, J, Sass, C, Probst, D, Werner, C, Leavitt, BR, Coleman, A, Raymond, L, Wheelock, V, Tempkin, T, Baynes, K, Hermanowicz, N, Niswonger, S, Haske-Palomino, M, Bordelon, Y, Gratiano, A, Johnson, A, Corey-Bloom, J, Goldstein, J, Peavy, G, Geschwind, M, Gooblar, J, Barton, C, Fernandez, H, Rodriguez, R, Suelter, M, Daniels, M, Romrell, J, Swartz, C, Beglinger, L, Epping, E, Waterman, E, Smith, MM, Dubinsky, R, Dubinsky, H, Gray, C, Craufurd, D, Howard, E, Jones, M, Murphy, H, Anderson, K, Nickerson, C, De Santo, J, Rigaud, T, Zappala, N, Robottom, B, Singer, C, Quesada, M, Rodriguez-Spengler, K, Cardenache, RH, Reilmann, R, Bohlen, S, Hoelzner, E-M, Colcher, A, Maccarone, H, Altin, L, Siderowf, A, Greenamyre, TJ, Lucarelli, N, Ivanco, L, Marshall, F, Hickey, C, Deuel, L, Biglan, K, Sussmuth, SD, Orth, M, Trautmann, S, Eschenbach, C, Samii, A, Macaraeg, A, Zielonka, D, Ciesielska, A, Marcinkowski, JT, Sempolowicz, J, Karaskiewicz, H, O'Neill, C, Haq, I, Witkowski, G, Antczak, J, Rola, R, Richter, P, Rakowicz, M, Jachinska, K, Criswell, S, Deppen, P, Wharton, K, Mahant, N, McCusker, E, Griffith, J, Loy, C, Stewart, L, Fisher, D, Holt, D, Orme, C, Watts, A, Weber, J, White, K, Hauser, RA, Albin, R, Coffey, C, Fischer, W, Miyasaki, J, Investigators, HORIZON, HORIZON Investigators of the Huntington Disease Study, Group, European Huntington's Disease, Network, Salvatore, Elena, DE MICHELE, Giuseppe, and Sacca', Francesco

Subjects
Male, medicine.medical_specialty, Indoles, Placebo-controlled study, Comorbidity, Placebo, Severity of Illness Index, law.invention, Placebos, Randomized controlled trial, Double-Blind Method, law, Internal medicine, medicine, Dementia, Humans, Donepezil, Adverse effect, Rivastigmine, Psychiatric Status Rating Scales, business.industry, Australia, Latrepirdine, Middle Aged, medicine.disease, Huntington Disease, Treatment Outcome, North America, Physical therapy, Female, Neurology (clinical), business, medicine.drug
Abstract

BACKGROUND Latrepirdine is an orally administered experimental small molecule that was initially developed as an antihistamine and subsequently was shown to stabilize mitochondrial membranes and function, which might be impaired in Huntington disease. OBJECTIVE To determine the effect of latrepirdine on cognition and global function in patients with mild to moderate Huntington disease. DESIGN Randomized, double-blind, placebo-controlled study. SETTING Sixty-four research centers in Australia, Europe, and North America. PATIENTS Four hundred three patients with mild to moderate Huntington disease and baseline cognitive impairment (Mini-Mental State Examination score, 10-26). INTERVENTION Latrepirdine (20 mg) vs matching placebo administered orally 3 times daily for 26 weeks. MAIN OUTCOME MEASURES The co-primary outcome measures were cognition as measured by the change in Mini-Mental State Examination score from baseline to week 26 and global function at week 26 as measured by the Clinician Interview-Based Impression of Change, plus carer interview, which ranges from 1 (marked improvement) to 7 (marked worsening). Secondary efficacy outcome measures included behavior, daily function, motor function, and safety. RESULTS The mean change in Mini-Mental State Examination score among participants randomized to latrepirdine (1.5-point improvement) did not differ significantly from that among participants randomized to placebo (1.3-point improvement) (P = .39). Similarly, the distribution of the Clinician Interview-Based Impression of Change, plus carer interview did not differ significantly among those randomized to latrepirdine compared with placebo (P = .84). No significant treatment effects were detected on the secondary efficacy outcome measures. The incidence of adverse events was similar between those randomized to latrepirdine (68.5%) and placebo (68.0%). CONCLUSION In patients with mild to moderate Huntington disease and cognitive impairment, treatment with latrepirdine for 6 months was safe and well tolerated but did not improve cognition or global function relative to placebo. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00920946.

Published
2013

2. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

Author

Beal MF, Oakes D, Shoulson I, Henchcliffe C, Galpern WR, Haas R, Juncos JL, Nutt JG, Voss TS, Ravina B, Shults CM, Helles K, Snively V, Lew MF, Griebner B, Watts A, Gao S, Pourcher E, Bond L, Kompoliti K, Agarwal P, Sia C, Jog M, Cole L, Sultana M, Kurlan R, Richard I, Deeley C, Waters CH, Figueroa A, Arkun A, Brodsky M, Ondo WG, Hunter CB, Jimenez-Shahed J, Palao A, Miyasaki JM, So J, Tetrud J, Reys L, Smith K, Singer C, Blenke A, Russell DS, Cotto C, Friedman JH, Lannon M, Zhang L, Drasby E, Kumar R, Subramanian T, Ford DS, Grimes DA, Cote D, Conway J, Siderowf AD, Evatt ML, Sommerfeld B, Lieberman AN, Okun MS, Rodriguez RL, Merritt S, Swartz CL, Martin WR, King P, Stover N, Guthrie S, Watts RL, Ahmed A, Fernandez HH, Winters A, Mari Z, Dawson TM, Dunlop B, Feigin AS, Shannon B, Nirenberg MJ, Ogg M, Ellias SA, Thomas CA, Frei K, Bodis-Wollner I, Glazman S, Mayer T, Hauser RA, Pahwa R, Langhammer A, Ranawaya R, Derwent L, Sethi KD, Farrow B, Prakash R, Litvan I, Robinson A, Sahay A, Gartner M, Hinson VK, Markind S, Pelikan M, Perlmutter JS, Hartlein J, Molho E, Evans S, Adler CH, Duffy A, Lind M, Elmer L, Davis K, Spears J, Wilson S, Leehey MA, Hermanowicz N, Niswonger S, Shill HA, Obradov S, Rajput A, Cowper M, Lessig S, Song D, Fontaine D, Zadikoff C, Williams K, Blindauer KA, Bergholte J, Propsom CS, Stacy MA, Field J, Mihaila D, Chilton M, Uc EY, Sieren J, Simon DK, Kraics L, Silver A, Boyd JT, Hamill RW, Ingvoldstad C, Young J, Thomas K, Kostyk SK, Wojcieszek J, Pfeiffer RF, Panisset M, Beland M, Reich SG, Cines M, Zappala N, Rivest J, Zweig R, Lumina LP, Hilliard CL, Grill S, Kellermann M, Tuite P, Rolandelli S, Kang UJ, Young J, Rao J, Cook MM, Severt L, and Boyar K

Subjects
Aged, Antioxidants metabolism, Dose-Response Relationship, Drug, Double-Blind Method, Early Diagnosis, Female, Humans, Male, Middle Aged, Parkinson Disease enzymology, Prospective Studies, Treatment Outcome, Ubiquinone administration & dosage, Ubiquinone blood, Antioxidants administration & dosage, Parkinson Disease diagnosis, Parkinson Disease drug therapy, Ubiquinone analogs & derivatives
Abstract

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit., Objective: To examine whether CoQ10 could slow disease progression in early PD., Design, Setting, and Participants: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation., Interventions: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E., Main Outcomes and Measures: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo., Results: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo)., Conclusions and Relevance: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit., Trial Registration: clinicaltrials.gov Identifier: NCT00740714.

Published
2014
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