Cornelia Kamp

Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

IMPORTANCE There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. RESULTS The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00449865.

A randomized clinical trial of CPI-1189 for HIV-associated cognitive-motor impairment.

Background: CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor-α (TNFα) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease. Objective: To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive–motor impairment. Methods: Sixty-four subjects with mild to moderate HIV-associated cognitive–motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment. Results: The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z-scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day (p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement. Conclusions: CPI-1189 was well tolerated in HIV subjects with cognitive–motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.

A responsive outcome for Parkinson's disease neuroprotection futility studies

Futility studies are designed to test new treatments over a short period in a small number of subjects to determine if those treatments are worthy of larger and longer term studies, or if they should be abandoned. An appropriate outcome measure for a neuroprotection futility study in Parkinsons disease (sensitive to tracking disease progression in the short‐term) has not been determined. Data sets from three clinical trials were used to compare Parkinsons disease outcome measures. Total Unified Parkinsons Disease Rating Scale (UPDRS; Mentation + Activities of Daily Living + Motor) change and Motor plus Activities of Daily Living UPDRS change, measured in untreated patients, required the smallest sample sizes of all the outcome measures explored. Other outcomes (UPDRS Motor, UPDRS Activities of Daily Living, and time to need levodopa) required somewhat larger sample sizes. Futility designs in Parkinsons disease are feasible in terms of short duration and small sample size requirements, and this design is being applied in two ongoing Parkinsons disease studies to select agents for future larger and longer term neuroprotection studies. Ann Neurol 2005;57:197–203

A randomized, placebo-controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster.

ABSTRACT Although acute pain in patients with herpes zoster can be severe and has a substantial impact on health‐related quality of life, there have been no randomized clinical trials of oral medications specifically for its ongoing treatment. A randomized clinical trial was conducted in which 87 subjects ⩾50 years of age with herpes zoster within 6 calendar days of rash onset and with worst pain in the past 24 h ⩾ 3 on a 0–10 rating scale initiated 7 days of treatment with famciclovir in combination with 28 days of treatment with either controlled‐release (CR) oxycodone, gabapentin, or placebo. Subjects were evaluated for adverse effects of treatment, acute pain, and health‐related quality of life. The results showed that CR‐oxycodone and gabapentin were generally safe and were associated with adverse events that reflect well‐known effects of these medications. Discontinuing participation in the trial, primarily associated with constipation, occurred more frequently in subjects randomized to CR‐oxycodone (27.6%) compared with placebo (6.9%). Treatment with CR‐oxycodone reduced the mean worst pain over days 1–8 (p = 0.01) and days 1–14 (p = 0.02) relative to placebo but not throughout the entire 28‐day treatment period as pain resolved in most subjects. Gabapentin did not provide significantly greater pain relief than placebo, although the data for the first week were consistent with a modest benefit. By demonstrating that CR‐oxycodone is safe, generally adequately tolerated, and appears to have efficacy for relieving acute pain, the results of this clinical trial provide a foundation for evidence‐based treatment for acute pain in herpes zoster.

Impact of pramipexole on the onset of levodopa-related dyskinesias

Dyskinesias are a major complication of dopaminergic therapy in the long‐term treatment of Parkinsons disease. In the CALM‐PD trial, subjects were initially randomized to levodopa or pramipexole and could later add levodopa if needed. After adjusting for disease duration and daily levodopa dosage, the incidence of dyskinesias after initiating levodopa was not significantly different among subjects initially randomized to levodopa and those initially randomized to pramipexole.

Evidence-based clinical trial design for chronic pain pharmacotherapy: A blueprint for ACTION

a Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA b Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA c Center for Human Experimental Therapeutics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA d Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA e Analgesic Solutions, Natick, MA, USA f Tufts University, Boston, MA, USA g California Pacific Medical Center, San Francisco, CA, USA h United States Food and Drug Administration, Bethesda, MD, USA i Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA j Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

Design innovations and baseline findings in a long-term parkinson’s trial: The national institute of neurological disorders and stroke exploratory trials in parkinson’s disease long-term study-1

Based on the preclinical data and the results of a phase II futility study, creatine was selected for an efficacy trial in Parkinsons disease (PD). We present the design rationale and a description of the study cohort at baseline. A randomized, multicenter, double‐blind, parallel‐group, placebo‐controlled phase III study of creatine (10 g daily) in participants with early, treated PD, the Long‐term Study–1 (LS‐1), is being conducted by the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinsons Disease network. The study utilizes a global statistical test (GST) encompassing five clinical rating scales to provide a multidimensional assessment of disease progression. A total of 1,741 PD participants from 45 sites in the United States and Canada were randomized 1:1 to either 10 g of creatine/day or matching placebo. Participants are being evaluated for a minimum of 5 years. The LS‐1 baseline cohort includes participants treated with dopaminergic therapy and generally mild PD. LS‐1 represents the largest cohort of patients with early treated PD ever enrolled in a clinical trial. The GST approach should provide high power to test the hypothesis that daily administration of creatine (10 g/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5‐year follow‐up visit against the background of dopaminergic therapy and best PD care.

Intranuclear rods in severe congenital nemaline myopathy

We compared the muscle pathology and clinical course in eight patients with congenital nemaline myopathy. An abundance of large intranuclear rods was present in the muscle fibers of one patient with a rapid, fatal course. Intranuclear rods were not present in the muscles of seven patients with a benign course. The large intranuclear rods and the smaller sarcoplasmic rods were similar ultrastructurally and exhibited positive immunoperoxidase staining with anti-β-actinin antibodies. The accumulation of β-actinin within myonuclei may reflect a severe disturbance of normal intracellular processes regulating myofibrillar synthesis. Since two previously reported infants with intranuclear nemaline rods also had a fatal outcome, the presence of intranuclear rods may represent a marker for a severe form of congenital nemaline myopathy.

Self-reported adherence versus pill count in Parkinson's disease: the NET-PD experience.

To compare the Morisky medication adherence questionnaire to pill counts as measures of adherence in the NET‐PD futility clinical trials. Background: Like in other chronic diseases, non‐adherence with medications occurs in Parkinsons disease (PD), although nonadherence has not been of significant concern in most PD clinical trials. The most common approach to assessment is to do a pill count at each visit. The simple, 4‐question Morisky medication adherence questionnaire may provide an alternative approach to monitoring treatment adherence in PD.

Caffeine consumption and risk of dyskinesia in CALM‐PD

Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa‐induced dyskinesia.