Clinical Trials Update: Where Do We Go from Here?

h1 class=”calibre8″>25 Clinical Trials Update: Where Do We Go from Here?

Jetan H. Badhiwala and Michael G. Fehlings

Abstract

Research in spinal cord injury (SCI) first entered the arena of clinical trials just over 30 years ago, commencing with the National Acute Spinal Cord Injury Study (NASCIS) I trial. Since then, there has been a flurry of trial activity in the field, spurred by the devastating cost of SCI to patients and families, and the economic footprint on society at large. Many of these trials have stirred controversy and have attracted criticism for their methodological shortcomings. This chapter provides a critical review of past and current clinical trials in SCI, in particular the findings of prospective randomized controlled trials, the difficulties encountered, and lessons learned that can be applied to future trials.

Keywords: spinal cord injury, randomized controlled trial, trial design, outcomes, patient selection, neuroprotective agents, quality-of-life indices, surgical decompression

25.1 Randomized Controlled Trials

25.1.1 Neuroprotection

Neuroprotective strategies attempt to counteract one or more of the secondary injury mechanisms in spinal cord injury (SCI). ¹^,² To date, nine randomized controlled trials (RCTs) examining neuroprotective agents in SCI have been published (▶ Table 25.1).

Methylprednisolone, Naloxone, and Tirilazad

Three North American and one Japanese trials evaluated the efficacy of methylprednisolone (MP), theorized to block peroxidation of neuronal membrane lipids early in the secondary injury cascade following SCI. ³

NASCIS I

The results of the National Acute Spinal Cord Injury Study (NASCIS) I trial ⁴ were published in 1984. It was the first RCT to evaluate the effect of a potential neuroprotective drug in acute SCI, and ushered in the clinical trial era of SCI. This was a multicenter, double-blinded RCT comparing two intravenous (IV) MP treatment protocols: (1) a high-dose protocol consisting of a 1,000-mg bolus at admission and daily thereafter for 10 days (11,000 mg total); or (2) a low-dose protocol consisting of a 100-mg bolus at admission and daily thereafter for 10 days (1,100 mg total). A total of 330 patients with acute SCI were enrolled from 1979 to 1981. No difference was noted in neurological recovery of motor function or pinprick and light touch sensation at 6 weeks or 6 months. There was also no significant difference in mortality. However, wound infections at both trauma and operative sites were greater in the high-dose group (risk ratio [RR] 3.55; 95% confidence interval [CI], 1.20–10.59). It is important to recognize that NASCIS I was published in an era where corticosteroid use in acute SCI was ubiquitous, despite the lack of hard clinical evidence of benefit. There was a perceived lack of equipoise with regard to the benefit of corticosteroids, and this raised ethical concerns for randomizing patients to a non-MP arm. For this reason, a placebo control was not included. By failing to show a “dose response,” and instead finding potential harm with higher-dose MP, the results of NASCIS I raised questions on the practice of routinely using corticosteroids in acute SCI. Nonetheless, the absence of a placebo control meant this study did little to address the absolute safety and efficacy of MP treatment in acute SCI. Moreover, subsequent data from animal studies suggested the peak serum MP concentrations obtained with the high-dose regimen would have been inadequate to produce a neuroprotective effect. ⁵

NASCIS II

The shortcomings of NASCIS I prompted the NASCIS II trial, ⁶ which began in May 1985. The results of NASCIS I overturned prevailing dogma and provided equipoise, allowing use of a placebo control group in NASCIS II. Patients were randomized to MP, the opioid receptor blocker naloxone, or a placebo. NASCIS II used a higher dose of MP consisting of a 30 mg/kg bolus at admission followed by an infusion of 5.4 mg/kg/hour for the subsequent 23 hours. Naloxone was given as a bolus of 5.4 mg/kg and then a 4.0 mg/kg/hour infusion for the next 23 hours. The results of NASCIS II were published in 1990. A total of 487 patients were randomized. The primary analysis of neurological recovery at 6 months revealed improvements in pinprick and light touch sensation among patients receiving MP, but no differences in motor recovery. However, the analysis was stratified to compare those receiving treatment before versus after 8 hours. Those patients who had received MP within 8 hours of injury had significantly better motor and sensory recovery compared to placebo. This applied to both complete and incomplete injuries. Motor scores in the MP group improved by an additional 4.8 points as compared to placebo (p = 0.03). Morbidity and mortality were similar across all three treatment groups, but there was a nonsignificant trend toward more frequent wound infections in the MP group (7.1%) compared to placebo (3.6%). This was a landmark paper. The uptake was profound, and the publication and dissemination of these results led to widespread adoption of the “NASCIS II Protocol” for acute SCI, which was almost considered standard of care. ⁷ However, the trial went on to generate substantial controversy, including alleged nontransparency of analysis and misinterpretation of results. ⁷^,⁸^,⁹^,¹⁰ A consistent criticism levied against NASCIS II is that the primary analysis was negative, and a treatment benefit was only seen in a subgroup analysis. ¹¹ Moreover, subsequent studies, as discussed below, have failed to reproduce the results of NASCIS II, although these have suffered from important methodological limitations, as we have published previously. ⁵

NASCIS III

NASCIS III ¹² was borne out of the unresolved question about the optimal duration of MP treatment and parallel preclinical data advancing our understanding of the duration of secondary injury mechanisms post-SCI. The question was whether a longer duration of MP treatment (48 hours) would afford greater neuroprotection and better neurological outcomes than the standard 24-hour regimen, while remaining safe. NASCIS III did not have a placebo arm given the positive results of NASCIS II. A total of 499 patients were randomized to either (1) a 48-hour MP protocol (30 mg/kg bolus followed by 5.4 mg/kg/hour); (2) a 24-hour MP protocol (30 mg/kg bolus followed by 5.4 mg/kg/hour); or (3) a 2.5 mg/kg bolus infusion of tirilazad (a 24-amino steroid shown in animal studies to have neuroprotective potential) every 6 hours for 48 hours. In the overall analysis, the 48-hour MP group showed improved motor recovery at 6 months, though this did not reach statistical significance (p = 0.07). Mortality was comparable; however, the 48-hour group had an increased risk of severe pneumonia (p = 0.02) and severe sepsis (p = 0.07). In the timing-related secondary analysis, for patients receiving treatment initiated 3 to 8 hours after injury, the 48-hour MP group had an additional 6 points in motor recovery at 6 months, as compared to the 24-hour MP group (p = 0.01). The authors concluded that patients who receive MP within 3 hours should be maintained on MP for 24 hours, whereas those initiated on therapy 3 to 8 hours after injury should receive the 48-hour protocol, accepting a potentially greater risk of infectious complications.

Other MP Trials

In a Japanese study, Otani et al ¹³ randomly assigned 158 patients either to the NASCIS II MP protocol, started within 8 hours of injury, or to standard medical care. Patients treated with MP experienced an additional 3.9 points in motor recovery compared to the control group on average, although this did not reach statistical significance. However, concerns regarding losses to follow-up and inadequate blinding threaten the validity of these findings. ⁵ Matsumoto et al ¹⁴ evaluated complication occurrence in 46 patients with cervical SCI randomized to either the NASCIS II MP regimen or a placebo. The MP group had a higher rate of pulmonary (p = 0.009) and gastrointestinal (p = 0.036) complications. A criticism with this trial is that the treatment groups were substantially unbalanced, with a disproportionately high proportion of less severe injuries (Frankel D) in the placebo group.

GM1 Ganglioside

The initial trial of GM1 (monosialotetrahexosylganglioside) ¹⁵ ganglioside was published in 1991. This was a single-center, randomized, double-blinded, placebo-controlled pilot study that evaluated the safety and efficacy of GM1 ganglioside as a neuroprotective agent in acute SCI. A total of 37 patients were enrolled between 1986 and 1987. Patients received 100 mg of either GM1 ganglioside or placebo intravenously per day for 18 to 32 doses, with the first dose given within 72 hours of injury. The authors found improved Frankel grades (p = 0.034) and American Spinal Cord Injury Association (ASIA) motor scores (p = 0.047) at 1-year follow-up in the GM1 ganglioside group compared to the placebo group, with no difference in adverse events. This single-center pilot study set the stage for the later multicenter trial of GM1 ganglioside. ¹⁶ This study enrolled 760 patients with ASIA A, B, C, and D injuries from 1992 to 1997. Patients were randomized to either 100 mg GM1 ganglioside, 200 mg GM1 ganglioside, or placebo initiated within 72 hours of injury and given daily for 56 days. The primary efficacy outcome was “marked recovery,” defined as two grades of improvement on the modified Benzel scale, at 26 weeks. The primary analysis was negative, although there was a nonsignificant trend favoring treatment in a subgroup analysis of patients with ASIA B injuries. Interestingly, the GM1 ganglioside group recovered function earlier, so that at 8 weeks (at the conclusion of therapy), the primary outcome favored the treatment groups. However, the control group “caught up” over the course of follow-up.

TRH

On the basis of preclinical data demonstrating improved long-term behavioral recovery with thyrotropin-releasing hormone (TRH) administered post-SCI, ¹⁷ Pitts et al ¹⁸ randomized 20 patients with SCI within 12 hours of injury to TRH or placebo. The trial was double-blinded. Patients were stratified by complete or incomplete injury. The treatment group received a 0.2 mg/kg IV bolus of TRH followed by a 0.2 mg/kg/hour infusion over 6 hours; the placebo group received an equal volume of saline. The authors found no treatment effect in the complete injury group. In patients with incomplete SCI, the TRH-treated group had significantly higher motor, sensory, and Sunnybrook scores than the placebo group. Unfortunately, the results of this trial have not been replicated.

Nimodipine

One of the common final pathophysiological mechanisms in SCI is ischemia and associated vascular changes. Nimodipine is a calcium channel blocker with vasodilatory effects. Experimental models of SCI found nimodipine reduced the decrease in spinal cord blood flow in the proximity of the traumatic lesion. ¹⁹^,²⁰ This provided the impetus for a randomized trial of nimodipine in human SCI. In France, 106 patients with SCI were randomized to one of four groups: nimodipine (0.015 mg/kg/hour for 2 hours followed by 0.03 mg/kg/hour for 7 days), MP (NASCIS II dose), nimodipine plus MP, or neither agents. ²¹ An effort was made to treat patients requiring surgical decompression as early as possible. The results of this trial were published in 2000. No treatment benefit was observed, and all treatment groups had similar neurological recovery, as measured by ASIA scores, to placebo. Similar to the NASCIS studies, this trial found evidence of greater infectious complications in the MP group. Early surgery (<8 hours) did not influence neurological outcome relative to surgery at the 8- to 24-hour mark, although patients were not randomized according to early surgery.

Gacyclidine

Another French study evaluated gacyclidine. An important secondary injury mechanism in SCI is neuronal release of excitotoxic glutamate, which results in abnormal levels of Ca²⁺ influx and eventually local cell death. ²²^,²³ Gacyclidine is an N-methyl-D-aspartate (glutamate receptor) antagonist with the ability to prevent glutamate-induced neuronal death. ²⁴ A clinical trial of gacyclidine for SCI was undertaken and the results published in 2003. ²⁵ There were strict inclusion and exclusion criteria which included: male or nonpregnant female, age 18 to 65 years, weight < 110 kg, maximum ASIA motor score 15 points for most severely injured lower limb, normal consciousness, documented Glasgow Coma Scale (GCS) score, able to receive first injection of gacyclidine within 2 hours of injury, able to undergo decompression surgery within 8 hours, and controlled blood pressure (systolic blood pressure no lower than 90 mm Hg for more than 15 minutes) prior to injection of drug. Patients were randomized to one of four groups: placebo or one of three doses of gacyclidine (0.005, 0.010, or 0.020 mg/kg). The drug was administered as early as possible within 2 hours of injury and again at 4 hours after the first injection. A total of 272 patients were evaluated. No significant difference was observed in ASIA or functional independence measurement (FIM) scores between any of the treatment or placebo groups at 1 year.

Minocycline

The antibiotic minocycline has been found to have neuroprotective properties in preclinical studies. ²⁶ In the context of SCI, it has been found to improve neurological recovery owing to reduced apoptosis of oligodendrocytes and microglia. ²⁷^,²⁸ Casha et al ²⁹

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