Creatine for amyotrophic lateral sclerosis/motor neuron disease

 

Abstract

Background

Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS). Results from human trials, however, have been mixed. Given conflicting results regarding creatine's efficacy, we conducted a systematic review.

Objectives

To systematically examine creatine's efficacy in prolonging ALS survival and in slowing ALS disease progression.

Search methods

We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 4, 2009), MEDLINE and EMBASE in October 2009 for any trial involving creatine in the treatment of ALS. We also contacted experts in the field for any additional studies.

Selection criteria

Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and percent predicted forced vital capacity (FVC) over time.

Data collection and analysis

Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study.

Main results

We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi² = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054).

Authors' conclusions

In patients already diagnosed with clinically probable or definite amyotrophic lateral sclerosis (ALS), creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALS functional rating revised scores (ALSFRS-R) progression or percent predicted forced vital capacity (FVC) progression.

 

Plain language summary

Creatine for amyotrophic lateral sclerosis/motor neuron disease

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease that results in widespread paralysis and shortened life. Recently, a naturally-occurring organic acid called creatine has gained attention as a potential therapy for ALS/MND. However, human trials have shown mixed results thus far. Therefore, we systematically reviewed all available clinical trial evidence as of October 2009 to determine if creatine benefits or harms people with ALS/MND. This review included three well-designed clinical trials involving a total of 386 participants receiving either creatine or placebo. Overall, creatine was well-tolerated with no serious side effects. Using various statistical methods, we found that creatine at a dose of 5 to 10 g per day did not improve ALS survival or slow ALS progression in any meaningful way. There was a hint that creatine may slightly worsen breathing ability, but this may have just been misleading statistical variability.

 

摘要

背景

以肌酸治療肌萎縮性脊髓側索硬化運動神經元疾病

肌酸是為腺酐三磷酸 (ATP) 製造過程中會自然產生的含氮有機酸，在肌萎縮性脊髓側索硬化症 (ALS) 的小鼠模型中也已被證實可增加小鼠的存活率。然而從人體試驗的結果來看其結果不一致。有關於評估肌酸的療效其結果分歧，故我們執行一個系統性的review。

目標

以系統性來評估肌酸對於延長ALS的存活率和減緩ALS疾病進展的療效。

搜尋策略

我們在Cochrane Neuromuscular Disease Group Trials Specialized Register、Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane醫學實證資料庫第四期，2009年) 、2009年10月的MEDLINE和EMBASE中搜尋了任何以肌酸治療ALS有關的研究試驗。我們也聯繫專精此領域的專家尋求是否有更進一步的研究可供參考。

選擇標準

在診斷有ALS病人身上分別以肌酸或安慰劑治療的隨機試驗。我們評估沒有氣管造口術病人的存活時間作為主要的結果；藉由評估肌萎縮性脊髓側索硬化症功能評估量表修訂版 (ALS functional rating revised scores，ALSFRSR) 的變化和隨著時間來預測肺活量 (forced vital capacity，FVC) 的百分比為ALS進展的測量項目以作為次要的結果。

資料收集與分析

由兩位作者獨立地篩選研究、評估風險偏差和擷取數據。我們從各項研究中得到每位受試者的數據並進行分析。

主要結論

我們納入的三項研究共有386名受試者，這些受試者隨機被分為每天給予肌酸5至10克，或安慰劑的組別。納入的三項研究都指出肌酸具有良好的耐受性，也沒有因肌酸所造成的腎衰竭或嚴重副作用的跡象產生。將資料合併並執行logrank statistical test，我們發現在此三項研究中都顯示肌酸組和安慰劑組的存活率在統計上彼此間無顯著差異 ((Chi2 = 0.09, P = 0.76) 。除此之外，將三項研究資料合併並執行linear mixed effects model後發現在ALSFRSR的斜率兩組間在統計上沒有顯著差異 (slope difference of +0.03 ALSFRSR/month in the creatine group; P = 0.76) 。有趣的是，將有包含FVC實驗結果的兩項研究資料合併並執行linear mixedeffects model，發現在肌酸組FVC的斜率有輕微惡化的趨勢 (slope　difference of −0.63 FVC/month in the creatine group) ，但沒有統計上的顯著差異 (P = 0.054) 。

作者結論

在臨床上診斷可能或明確患有肌萎縮性脊髓側索硬化症 (ALS) 的受測者其每天給予5 – 10克的肌酸治療對其存活率、ALSFRSR進展和預測FVC百分比的進展沒有統計上顯著性的效果。

翻譯人

本摘要由吳曉玲翻譯。

此翻譯計畫由臺灣國家衛生研究院 (National Health Research Institutes, Taiwan) 統籌。

總結

以肌酸治療肌萎縮性脊髓側索硬化運動神經元疾病: 肌萎縮性脊髓側索硬化症 (ALS) ，也稱為運動神經元疾病 (MND) ，是一個漸進的神經退化性疾病，會引起全身性癱瘓和縮短壽命。最近，肌酸為一個自然產生的有機酸已經獲得注意，因它具有治療ALSMND的潛力。然而，人類的試驗結果顯示以肌酸來治療的結果不如預期。因此，我們有系統地審查2009年10月所有可用的臨床試驗研究，以評估肌酸對患有ALSMND的病人所帶來的利與弊。這篇review包含三項有良好設計的臨床試驗共有386名受測者分別接受以肌酸或安慰劑的治療。整體而言，肌酸具有較好的耐受性，也無產生嚴重的副作用。利用各種統計方法，我們發現在每天給予肌酸劑量為5 – 10克後，評估對於ALS病人的存活率或減緩ALS的進展無有意義的改善。結果也發現，肌酸可能會輕微惡化呼吸的能力，但這可能只是統計變異所產生的誤導。