Recruitment of participants to a multiple sclerosis trial: the CombiRx experience.

BACKGROUND: and purpose Participant recruitment is central to all clinical trials. Any delay in recruitment affects the completion and ultimate success of the trial. We report our experience with patient screening and randomization in CombiRx, which may inform the design of other trials. CombiRx was a multicenter, phase III, double-blind, randomized clinical trial comparing the combined use of interferon beta-1a and glatiramer acetate to either agent alone in patients with relapsing-remitting multiple sclerosis (RRMS). This trial was launched in January 2005 in 69 centers in the United States and Canada under a co-operative agreement with the National Institute of Neurological Disorders and Stroke (NINDS). The goal was to recruit 1000 patients over 1.5 years after a 6-month start-up period. Instead, the investigators required 4.25 years to enroll 1008 patients. METHODS: During this trial, we assessed the effectiveness of various recruitment strategies, utility of rescreening prior screen failures, and potential factors and strategies used in study conduct, research, and infrastructure, all of which affected recruitment of participants and ultimately time to completion of CombiRx. We particularly were interested in the variability in time to site initiation between academic centers and private practice sites. RESULTS: Physicians who were directly involved in the medical care of patients with RRMS were the primary source of patients recruited to CombiRx. A flexible study design that allowed for rescreening of the initial screen failures after a period of time was useful due to the relapsing/remitting course of the disease. Academic centers took longer to implement the trial than the private practice centers, but once sites were approved for enrollment, there was no important difference in the number of participants enrolled. LIMITATIONS: The CombiRx trial was conducted during a period when multiple new medications were being tested, thus affecting the pace of recruitment and limiting ability to generalize our experiences. However, the lessons we learned about process are relevant. CONCLUSION: Participants can be enrolled successfully in a clinical trial for RRMS, but factors affecting the time to achieve the requirements needed to start screening can be unpredictable and problematic. Prospective planning by the sponsors and investigators, use of central institutional review boards (IRBs), master trial agreements and secure remote desktop access to the trial database may expedite trial implementation and participant recruitment. A good scientific research question with flexible study design and active involvement of the clinicians are important factors driving recruitment. Clinical trials can be implemented successfully both in private practices and at academic centers, a consideration when selecting sites.

Adding more muscle and nerve to clinical trials.

In this review we illustrate both the fundamentals and challenges of randomized clinical trials in neuromuscular disorders and suggest directions for prospective efforts to improve the design, conduct, rigor, and objectivity of these trials. Current research in clinical trials for neuromuscular disorders and key issues affecting these trials are reviewed. This perspective addresses the planning of clinical research, level of preclinical data needed to justify trials, patient recruitment and retention, and opportunities to access federal funding and infrastructure in support of clinical trials. The need for innovation in trial design and conduct, rigorous standards for the preclinical efficacy and safety data that support trial rationale, novel collaborative paradigms, objective interpretations of outcomes, and sharing of the lessons learned from trials in any one disorder among all neuromuscular trialists are imperative to improving the heretofore limited success in delivering novel, safe, and effective therapies to patients burdened by neuromuscular disorders.

Diabetic and non-diabetic lumbosacral radiculoplexus neuropathy.

BACKGROUND: Lumbosacral radiculoplexus neuropathy (LRPN) originally described in diabetic patients is a distinct clinical condition characterized by debilitating pain, weakness and atrophy most commonly affecting the proximal thigh muscles asymmetrically. The syndrome is usually monophasic and preceded by significant weight loss (at least more than 10 lbs). Though a self-limited condition, recovery is gradual with some residual weakness. Recent advances and research has provided new insights in the pathogenesis and thereby management of this syndrome. In this paper, we review the clinical and diagnostic features as well as discuss recent insights and treatment strategies along with our experience in the management of patients with diabetic and non-diabetic LRPN. MATERIALS AND METHODS: Literature in English published between 1953 and 2008 was searched in the MEDLINE and Pubmed database, maintained by the US National library of medicine and National institutes of health, using key words of diabetic amyotrophy, lumbosacral radiculoplexus neuropathy, diabetic proximal neuropathy, diabetic radiculopathy and diabetic lumbosacral plexopathy. In addition, literature reported in various textbooks on peripheral neuropathy was reviewed as well. OBSERVATION: The diagnosis relies mostly on clinical suspicion and characteristic electromyographic findings. The exact pathogenesis of the illness remains unknown, but there seems to be a component of immune-mediated inflammatory microvasculitis which causes secondary ischemia of the lumbosacral plexus. This has prompted a trial of immunosuppressive agents (like steroids) with an attempt to alter the course of the illness. A few reports have noted that immunosuppression when instituted early in the course of the illness (within three months of symptom onset) may hasten the recovery and improve symptoms. CONCLUSION: Though the exact mechanism of LRPN in diabetic and non-diabetic patients remains unknown, new evidence alludes to an underlying inflammatory vasculitic process. Early treatment with immunosuppressants may be beneficial in some cases, although the data available at this time is limited to a small cohort of patients. The decision is individualized weighing the risks and benefits in a given patient. Future research in this direction with double-blinded case-controlled studies is required to investigate this further.

The evaluation and management of patients with neuroleptic malignant syndrome.

NMS is a rare but fatal syndrome that needs to be considered in the perioperative period. Although many aspects remain unexplored and controversial, with greater awareness of the condition, new concepts are coming into light. Definitive treatment guidelines remain an important issue to be addressed. Efforts have been initiated in that direction and all cases can be reported on a toll-free hotline ( 1-888-667-8367) or online (www.nmsis.org).

Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: To describe the presentation and management of encephalitis due to human herpes 6 virus (HHV-6) in patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT), via retrospective chart review. METHODS: Of the 243 patients who underwent alloHSCT at the NIH Clinical Center during 2009 to 2011, we retrospectively analyzed 9 diagnosed with HHV-6 encephalitis post-alloHSCT. RESULTS: Eight men and 1 woman (aged 19-60 years) met diagnostic criteria for study inclusion. The median time from HSCT to initial symptoms was 21 days. All patients presented with altered mental status and headaches. Seven patients had amnesia and 2 presented with fever of unknown etiology. Four patients had clinical seizures during the disease course. Brain MRI within 7 days was normal in all patients. Repeat MRI after 7 days showed hyperintensity in the limbic area in 3 patients. On initial testing, CSF analysis indicated acellularity and normal or minimally elevated protein; presence of HHV-6 was detected by PCR. After 7 days, mildly elevated protein and minimal pleocytosis were noted. Ganciclovir, foscarnet, or valganciclovir alone or in combination was initiated with subsequent improvement. Four patients remained alive at 1 year posttransplant; 2 had persistent memory deficits. Presence of encephalitis was associated with higher mortality post-alloHSCT. CONCLUSION: High clinical suspicion and CSF PCR testing are important for early diagnosis of HHV-6 encephalitis post-HSCT. Abnormalities on brain MRI or CSF testing may be minimal and delayed. Diagnosis and management of HHV-6 encephalitis is challenging, and a larger prospective study is needed for further research.

Treatment of ocular symptoms in myasthenia gravis.

BACKGROUND: The choice between acetyl-cholinesterase inhibitors (AChE-Is) and steroids as symptomatic therapy for ocular symptoms in myasthenia is controversial. METHODS: Thirty-five patients with myasthenia and ocular symptoms were evaluated by a single investigator. The ocular-quantitative myasthenia gravis (QMG) score was determined at each visit. The longitudinal construct validity of the ocular-QMG was assessed. Treatment epochs on AChE-I therapy alone or on steroids were defined for each patient. Changes in ocular-QMG scores between the start and end of each treatment epoch as well as the proportion of subjects achieving remission of symptoms were documented. The frequency of steroid-induced side effects was documented. RESULTS: The longitudinal construct validity was favorable and comparable to that for the total QMG score. Eight patients were treated with AChE-I therapy alone, 6 were initially treated with AChE-I followed by steroids, and 21 received steroids ab initio. There were 14 epochs of AChE-I treatment and 27 epochs of steroid treatment. The mean improvement in ocular-QMG score was greater during the steroid epoch (3.6 +/- 2.4) than during the AChE-I epoch (1.1 +/- 1.9) (p = 0.0021). Complete resolution of ocular symptoms occurred in 29% of AChE-I treatment epochs and in 70% of steroid treatment epochs. The most common steroid-induced side effects observed were impaired glucose tolerance (67%) and reduced bone mineral density (20%). CONCLUSION: The ocular-quantitative myasthenia gravis score may be a useful tool for monitoring ocular symptom severity in myasthenia. Steroids appear to be more effective than acetyl-cholinesterase inhibitors. These findings warrant a more formal evaluation in a randomized controlled trial.