Treatment for familial amyotrophic lateral sclerosis/motor neuron disease

Michael Benatar; Jerome Kurent; Dan H Moore

doi:10.1002/14651858.CD006153.pub2

. 2009 Jan 21;2009(1):CD006153. doi: 10.1002/14651858.CD006153.pub2

Treatment for familial amyotrophic lateral sclerosis/motor neuron disease

Michael Benatar ^1,^✉, Jerome Kurent ², Dan H Moore ³

Editor: Cochrane Neuromuscular Group

PMCID: PMC7388919 PMID: 19160266

Abstract

Background

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a rare neurodegenerative disease. Approximately 5% to 7% of ALS/MND patients report a family history of a similarly affected relative. Superoxide dismutase‐1 gene mutations are the cause in about 20% of familial cases. In those with non‐familial (sporadic) ALS/MND the cause is unknown. Also unknown is whether people with familial and sporadic ALS/MND respond differently to treatment.

Objectives

To systematically review the literature and to answer the specific question: 'Is there a differential response to treatment between people with sporadic and familial forms of ALS?'

Search methods

We searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central register of Controlled Trials (CENTRAL), MEDLINE and EMBASE for randomized controlled trials (RCTs). Two review authors read the titles and abstracts of all articles and reviewed the full text of all possibly relevant articles. We scanned references of all included trials to identify additional relevant articles. For all trials eligible for inclusion we contacted the authors to request the necessary raw data.

Selection criteria

Studies had to meet two criteria: (a) randomized controlled study design, and (b) inclusion of participants with both familial and sporadic ALS/MND.

Data collection and analysis

We attempted to contact authors of all trials that met inclusion criteria. We obtained data regarding ALS/MND type (sporadic versus familial), treatment assignment (active versus placebo), survival and ALS Functional Rating Scale (ALSFRS) scores for included RCTs.

Main results

Five RCTs involving 895 sporadic and 52 familial ALS/MND participants were included. There was no statistical evidence for a differential response to treatment in participants with familial ALS/MND compared to those with sporadic ALS/MND. The pooled estimate of the hazard ratio for the interaction term (treatment x familial ALS) suggested a more beneficial response with respect to survival among participants with familial ALS/MND, but the result was not statistically significant. Pooled estimates of the rate of decline on the ALSFRS suggested a slightly better overall response to treatment among those with familial ALS/MND, but the result was not statistically significant.

Authors' conclusions

Based on the available data, there is little evidence for a differential response to treatment among people with familial and sporadic ALS/MND. Future randomized controlled trials should document whether people with familial ALS/MND are included and the presence or absence of a mutation in an ALS susceptibility gene amongst those with familial ALS/MND.

Plain language summary

Treatment for familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) and Lou Gehrig's disease, is a rare disease in which degeneration of motor nerves leads to progressive weakness and wasting of muscles. For the most part, the cause of ALS is unknown. In a small proportion of cases there is a family history of ALS/MND and in an even smaller proportion, the disease is known to result from a change in one of several genes including SOD1, TDP‐43 and FUS. An understanding of the genetic basis for one familial form of ALS/MND has permitted the construction of an animal model of ALS/MND (the SOD1 mouse) that has been used extensively to study potential therapeutic agents for the human disease. None of the drugs found to be effective in the mouse have translated into therapeutic benefits for humans with ALS/MND. There are several possible explanations for this finding, one of which is that people with familial and sporadic ALS may respond differently to the same treatment and that the SOD1 mouse may be a better model of familial ALS (or at least familial ALS due to mutations in the SOD1 gene) than it is of sporadic ALS. In an effort to begin to address this question, this review was undertaken in order to ask whether or not people with the familial form of the disease respond differently to treatment compared to people with the sporadic (or non‐familial) form of ALS/MND.

We identified all randomized controlled trials in ALS/MND and wrote to the authors to request the data needed to complete this review. Although many more studies were eligible for inclusion, only five authors were willing and able to share the data from their individual randomized controlled trials. Based on the analyses of these data, we find no evidence to support a statistically significant difference in the response to treatment between people with the familial and sporadic forms of ALS/MND.

Background

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder, characterized by loss of motor neurons in the spinal cord, brainstem and cerebral cortex, that leads to progressive muscle weakness, wasting and ultimately death from respiratory paralysis within three to five years of disease onset. The term motor neuron disease (MND) is sometimes used synonymously with ALS, but may also be used as a more encompassing term that includes progressive bulbar palsy, progressive muscular atrophy and primary lateral sclerosis. Most cases of ALS are sporadic and the etiology is unknown. Familial ALS (fALS), defined by the presence of at least two affected family members (Valdmanis 2008), accounts for approximately 5% to 7% of cases (Chio 2008; Forsgren 1983; Lopez‐Vega 1988; Norris 1993) and mutations in the Cu/Zn superoxide dismutase‐1 (SOD1) gene are present in about 20% of people with fALS (Cudkowicz 1997; Orrell 1997). More recently, mutations in other genes such as TDP‐43 (Van Deerlin 2008) and FUS (Kwiatkowski 2009; Vance 2009), have been identified as important causes of fALS.

The recognition that fALS may result from mutations in the SOD1 gene has led to the development of an animal model of ALS that has been used to examine the effects of potential therapeutic agents (Gurney 1994). Unfortunately, the success of these agents in prolonging survival in the SOD1 model of ALS/MND has not translated into effective therapies for people with ALS/MND. One possible explanation is that the SOD1 mouse is a better model of familial (or at least SOD1 positive familial) ALS than it is of sporadic ALS (sALS) and that people with familial and sporadic ALS may respond differently to the same treatment (Benatar 2006).

To the best of our knowledge there are no completed treatment trials that have specifically focused on people with fALS, but these participants were not always systematically excluded from the large multicenter treatment trials that have been performed in the broader ALS population (BDNF Study 1999; Beghi 2000; Bensimon 1994; Bensimon 2002; Borasio 1998; CNTF Study 1996; Cudkowicz 2003; Desnuelle 2001; Groeneveld 2003; Lacomblez 1996; Lai 1997; Meininger 2004; Miller 2001; Shefner 2004). Within the last several years, however, three trials have been initiated (and are currently ongoing) that focus specifically on people with fALS due to mutations in the SOD1 gene (Arimoclomol, ISIS 333611, Pyrimethamine). These include a phase II/III randomized controlled trial (RCT) of arimoclomol, a phase I/II open‐label trial of pyrimethamine and a phase I RCT of intrathecal anti‐sense oligonucleotides.

Objectives

The purpose of this systematic review was to assemble the data that pertain to participants with fALS from the large ALS treatment trials in order to address a specific question: 'Is there a differential response to treatment between people with the sporadic and familial forms of ALS'?

Methods

Criteria for considering studies for this review

Types of studies

We included all randomized controlled trials (RCTs) and quasi‐randomized trials that included people with familial ALS.

Types of participants

To be included in this review participants had to have ALS, based on criteria defined by the authors of each individual RCT. We based the designation of a participant as having familial ALS on the evaluation of the investigators in each individual study. People of any age and either gender were eligible for inclusion in this review.

Types of interventions

We considered any drug treatment compared to either no treatment or a placebo. We also included studies that examined comparisons or combinations of these treatments.

Types of outcome measures

Primary outcomes

We selected survival time as the primary outcome as this was the most commonly used outcome among the studies for which data were available. Survival time is typically measured from the time of trial enrollment/randomization.

Secondary outcomes

We selected the rate of decline on the ALS Functional Rating Scale (ALSFRS) as the secondary outcome measure.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Neuromuscular Disease Group Specialized Register using the following search terms: 'amyotrophic lateral sclerosis' or 'motor neuron disease' or 'motor neurone disease' or 'motoneurone disease' or 'MND' or 'ALS'.

We adapted this strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2010 in the Cochrane Library), MEDLINE ( January 1966 to June 2010) and EMBASE (January 1980 to June 2010).

Papers published in any language were eligible for inclusion and we made every effort to obtain English translations of any RCTs published in other languages.

The search strategies are in the appendices: MEDLINE Appendix 1, EMBASE Appendix 2 and the Cochrane Central Register of Controlled Trials Appendix 3.

Searching other resources

We reviewed references within the articles identified by this search to identify additional studies. We also contacted authors and known experts in the field, and approached pharmaceutical companies to identify unpublished studies.

Data collection and analysis

Selecting trials for inclusion

Two review authors independently reviewed the titles and abstracts from the electronic search in order to identify studies that might be relevant to the review. We read the full text of all studies identified in this way. A decision was made regarding their suitability for inclusion in the review based on whether they met the pre‐specified inclusion criteria. We resolved disagreement between the two authors by discussion. Review authors were not blinded to authors' names, institutional affiliation or journals of publication.

Assessment of methodological quality

Both review authors independently assessed studies for their methodological quality according to the methods set out in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008), with particular attention to (1) randomization, (2) allocation concealment, (3) blinding of participants, personnel and outcome assessors, (4) loss to follow up and completeness of data included in the analyses, (5) the selective reporting of outcome measures and (6) other potential threats to validity.

Data extraction

We did not anticipate that any of the data required for this systematic review would have been published and expected to contact the lead investigators, sponsors or both of each RCT identified by the literature search in order to request the primary data. This expectation was borne out. When investigators were willing to provide data, we requested as many of the following data items as were available:

study subject identifier;
age;
gender;
time since onset of ALS;
time since diagnosis of ALS;
site of disease onset (limb or bulbar);
concurrent riluzole treatment for non‐riluzole studies (yes or no);
type of ALS (sporadic or familial);
active treatment agent and dose;
control treatment agent;
treatment group assignment;
primary outcome measure at baseline and at each follow‐up time point;
secondary outcome measures at baseline and at each follow‐up time point; and
adverse events.

Analysis

We obtained raw data from five studies: the Northeastern ALS (NEALS) Consortium celecoxib (Cudkowicz 2006), creatine (Shefner 2004), topiramate (Cudkowicz 2003) and arimoclomol (Cudkowicz 2008) studies, and the Dutch creatine study (Groeneveld 2003). Each dataset had information on familial versus sporadic ALS, ALS Functional Rating Scale (ALSFRS) (the older 10‐item version with a scale of 0 to 40) and survival time.

For survival we used a Cox proportional hazards model to assess the following factors: treatment group (treated versus placebo), ALS type (familial versus sporadic) and the interaction between treatment group and ALS type with stratification by study. Stratification by study was necessary because different treatments were given in each study and survival was statistically significantly better in the NEALS celecoxib study than in the other four.

For ALSFRS, we fitted the data with a linear mixed‐effects model. The model included fixed‐effect terms for study, treatment arm, ALS type (familial or sporadic) and the interaction between treatment and ALS type. Random‐effects terms for patient intercept and slope (rate of decline) were also included in the model.

Results

Description of studies

Results of the search

The original search yielded 6208 citations. The updated literature search identified an additional 2382 citations (1644 in February 2009 and 738 in July 2010). Two review authors read the titles, and where relevant the abstracts, of all of these references. Each author identified a subset of references that were considered potentially eligible for inclusion. The subsets of references identified by each review author were combined to yield a total of 145 references that were then subjected to full manuscript review by each author. From among these 145 references, 100 randomized controlled trials (RCTs) were identified.

Included studies

Five studies are included in this review (see the 'Characteristics of included studies' table). Four of these studies were included in the previous version of this review; the fifth is new to this update (Cudkowicz 2008). Each of these was a randomized, double‐blind, placebo‐controlled trial. Four of these trials were conducted by the Northeastern ALS Clinical Trials Consortium in the United States and the fifth was conducted in the Netherlands. In two trials the active agent under investigation was creatine monohydrate (Groeneveld 2003; Shefner 2004). The active agents in the other three studies were celecoxib (Celebrex®) (Cudkowicz 2006), topiramate (Topamax®) (Cudkowicz 2003) and arimoclomol (Cudkowicz 2008). Each active agent was compared against placebo. Both active agents and placebo were administered orally in each study. Celecoxib was administered at a dose of 800 mg/day (Cudkowicz 2006), topiramate at the highest tolerated dose (maximum 800 mg/day) (Cudkowicz 2003), creatine in the NEALS study was dosed at 20 g per day for five days followed by 5 g per day (Shefner 2004), and the dose of creatine in the Dutch study was 10 g per day (Groeneveld 2003). Arimoclomol was administered at dosages of 75 mg, 150 mg and 300 mg per day (Cudkowicz 2008). The sample sizes of these studies ranged from 84 (NEALS arimoclomol study) (Cudkowicz 2008) to 300 (celecoxib study) (Cudkowicz 2006). The primary outcome measures were the rate of decline of arm megascore derived from the strength of eight arm muscles quantified using maximum voluntary isometric contraction (MVIC) in the topiramate (Cudkowicz 2003), celecoxib (Cudkowicz 2006) and NEALS creatine studies (Shefner 2004), and event (death, tracheostomy and persistent assisted ventilation‐free survival) in the Dutch creatine study (Groeneveld 2003). Tolerability and safety were the primary outcome measures in the trial of arimoclomol (Cudkowicz 2008).

Excluded studies

People with the familial form of ALS were specifically excluded from 26 studies. A further 15 studies did not include any participants with familial ALS (fALS) even though the inclusion/exclusion criteria for these studies had not formally excluded this group of people. Four studies did not keep track of whether participants had sporadic or familial ALS and nine studies included fewer than four participants with fALS. Application of these filters yielded 38 RCTs. Repeated efforts were made to contact the lead, senior authors or both, from the publications describing these RCTs. Methods of contact included email, telephone, fax, mailing address and in‐person requests where possible. No response to enquiries and requests for data was received for 17 studies. Eight authors replied, indicating that data were no longer available and a further eight refused to provide data (see the 'Characteristics of excluded studies' table).

Studies awaiting classification

A further eight studies have been identified and are awaiting classification. Since the nature of this review requires contact with the authors of all trials to request original trial data, there is a inevitably a long latency from literature search to analysis of data. In the interest of maintaining this review current, a decision was made to proceed with publication based on trial data received, pending request and receipt of data from the most recent trials. The characteristics of these outstanding trials are summarized in the table entitled Characteristics of studies awaiting classification.

Risk of bias in included studies

The five studies included in this review have a low risk of bias (see Figure 1 and the 'Characteristics of included studies' table). All were randomized, double‐blind, placebo‐controlled trials in which the details of randomization sequence, treatment allocation and blinding were well described. Analyses were all by intention‐to‐treat and included almost all (if not all) subjects who underwent randomization. These studies included relatively small numbers of participants with fALS and they were not evenly distributed between the treatment groups. The small sample size might contribute to random variability but should not introduce a source of bias.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Effects of interventions

In the five datasets there were 895 sporadic and 52 participants with fALS. The breakdown by study is shown in Table 1. Overall, 5.5% of participants had fALS/MND (range 3.7% to 13%). The number of deaths in each study by treatment group and type is shown in Table 2 and estimates for hazard ratios are shown in Table 3. None of the hazard ratios for treatment effects were statistically significant, in agreement with the original studies. There were no deaths among fALS participants in either the treatment or control group in the NEALS creatine study (Shefner 2004), so the hazard ratio for fALS could not be estimated. The interaction term, treatment x fALS, which tests whether the treatment effect differs for fALS compared to sporadic ALS (sALS), could not be estimated in the NEALS celecoxib (Cudkowicz 2006), creatine (Shefner 2004) and arimoclomol (Cudkowicz 2008) studies (Table 3). In the remaining studies the interaction term hazard ratio estimate was less than one for NEALS topiramate (Cudkowicz 2003) and greater than one for Groeneveld creatine (Groeneveld 2003), but neither significantly differed from 1.0. Thus, there is no statistical evidence for a differential response to treatment in fALS compared to sALS.

1. Study distribution of sporadic and familial cases.

Study	Sporadic ALS	Familial ALS	TOTAL
Celecoxib (NEALS) (Cudkowicz 2006)	281	19	300
Creatine (NEALS) (Shefner 2004)	90	4	94
Topiramate (NEALS) (Cudkowicz 2003)	283	11	294
Creatine (Dutch) (Groeneveld 2003)	168	7	175
Arimoclomol (NEALS)	73	11	84
TOTAL	895	52	947

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2. Distribution of people with ALS by study, treatment group, ALS genotype and survival status.

				Sporadic ALS		Familial ALS
Study	Treatment group	Total N	Duration of follow up	N	Deaths	N	Deaths
Celecoxib (NEALS) (Cudkowicz 2006)	Control	99	12 months	89	8	10	1
Celecoxib (NEALS) (Cudkowicz 2006)	Treated	201	12 months	192	18	9	0
Creatine (NEALS) (Shefner 2004)	Control	48	6 months	45	5	3	0
Creatine (NEALS) (Shefner 2004)	Treated	46	6 months	45	2	1	0
Topiramate (NEALS) (Cudkowicz 2003)	Control	97	12 months	92	27	5	2
Topiramate (NEALS) (Cudkowicz 2003)	Treated	197	12 months	191	47	6	1
Creatine (Dutch) (Groeneveld 2003)	Control	120	16 months	114	87	6	5
Creatine (Dutch) (Groeneveld 2003)	Treated	55	16 months	54	43	1	1
Arimoclomol (NEALS) (Cudkowicz 2008)	Control	22	16 weeks	18	0	4	0
Arimoclomol (NEALS) (Cudkowicz 2008)	Treated	62	16 weeks	55	3	11	1
Totals		947		895	240	52	11

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3. Hazard ratio estimates by study (95% confidence intervals).

	Hazard ratio
Study	Treatment	Familial ALS	Treatment x familial ALS
Celecoxib (NEALS) (Cudkowicz 2006)	1.13 (0.49 to 2.60)	1.04 (0.13 to 8.32)	Not estimable
Creatine (NEALS) (Shefner 2004)	0.39 (0.07 to 2.02)	Not estimable	Not estimable
Topiramate (NEALS) (Cudkowicz 2003)	0.84 (0.52 to 1.35)	1.28 (0.31 to 5.40)	0.53 (0.05 to 6.07)
Creatine (Dutch) (Groeneveld 2003)	1.03 (0.71 to 1.49)	0.69 (0.28 to 1.71)	2.70 (0.30 to 21.1)
Arimoclomol (NEALS) (Cudkowicz 2008)	∞ (no deaths in placebo group)	2.23 (0.23 to 21.5)	Not estimable

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By pooling the data and fitting with a Cox proportional hazard model stratified by study, we could estimate an overall hazard ratio for the interaction term (Table 4). The pooled estimate is less than 1.0 indicating that participants with familial fALS had a more beneficial response to treatment than participants with sALS . However, this estimated difference is far from reaching statistical significance (95% confidence interval 0.16 to 5.04).

4. Cox proportional hazards results.

Factor	Hazard ratio	Standard error	z	P > \|z\|	95% confidence interval
Treatment	0.79	0.12	‐1.5	0.13	0.58 to 1.07
Familial ALS	0.65	0.33	‐0.84	0450	0.23 to 1.78
Treatment x familial ALS	0.90	0.79	‐0.12	0.90	0.16 to 5.04

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Results from fitting the data to a linear mixed‐effects model are summarized in Table 5. Estimated slopes of the rate of decline of the ALSFRS (points per month) are largely similar across the different studies, although their estimated intercepts differed (results not shown). One notable exception is the slope estimate among the seven people with fALS treated with arimoclomol (Cudkowicz 2008) in which the ALSFRS is estimated to decline by ‐0.26 points/month (95% CI ‐1.15 to 0.64) (Table 5). This rate of decline in non‐significantly lower than the rates of decline amongst people with fALS in the other four studies (‐0.84 to ‐1.64 points/month). Estimates for the differential treatment effect in fALS compared to sALS alternated in sign with an estimate of 0.36 for the pooled data. This also indicates a slightly better response to treatment in fALS compared to participants with sALS, although the estimate is once again not statistically significant (95% confidence interval for pooled effect ranges from ‐0.13 to 0.84).

5. Estimates of slopes from linear mixed‐effects model ¹.

	Sporadic		Familial		Differential effect
Study	Control	Treated	Control	Treated	Estimate	95% confidence interval
Celecoxib (NEALS) (Cudkowicz 2006)	‐0.90	‐0.84	‐0.96	‐0.87	0.15	‐0.69 to .99
Creatine (NEALS) (Shefner 2004)	‐0.82	‐0.83	‐0.77	‐0.89	‐0.11	‐1.73 to 1.51
Topiramate (NEALS) (Cudkowicz 2003)	‐0.87	‐1.05	‐1.49	‐0.84	0.84	‐0.05 to 1.72
Creatine (Dutch) (Groeneveld 2003)	‐0.93	‐0.88	‐0.81	‐1.64	‐0.88	‐2.52 to 0.76
Arimoclomol (NEALS) (Cudkowicz 2008)	‐0.74	‐0.87	‐0.72	‐0.26	0.59	‐0.94 to 2.12
Pooled estimate	‐0.87	‐0.77	‐1.00	‐0.74	0.36²	‐0.13 to 0.84

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¹ Slope estimates describe the rate of decline of the ALSFRS‐R score (points/month)   ² Test for differential effect over all 5 studies: P = 0.15.

Discussion

This systematic review was undertaken in order to try to address the question of whether there is a differential response to treatment between people with the sporadic and familial forms of ALS/MND. It might reasonably be asked why this is an important question. The answer lies in the increasing recognition that ALS/MND may not be a single disease, but rather a syndrome of diverse etiologies and varying (although overlapping) clinical presentations. This is one reason for the relevance of asking whether people with the familial and sporadic forms of ALS/MND respond differentially to therapeutic agents. A second reason derives in part from the common practice of using data from the mouse model of ALS/MND, which is based on introduction of the SOD1 mutation into the mouse and which is perhaps more representative of familial than sporadic forms of ALS/MND. It might argued, for example, that a therapeutic agent that shows benefit in the animal model of the familial form of the disease might offer the greatest potential for benefit in human disease that is also attributable to a mutation in the SOD1 gene.

Summary of main results

Two analyses were performed to address the question of whether or not there is a differential response to treatment among people with the familial and sporadic forms of ALS/MND. The first analysis was based on the primary outcome (survival). The second analysis was based on the rate of decline of the ALSFRS.

Estimates of the hazard ratios (HR) of response to treatment (comparing people with familial ALS/MND (fALS/MND) to those with sporadic disease) in the individual studies vary from 0.53 in the NEALS topiramate study (Cudkowicz 2003) to 2.7 in the Dutch creatine study (Groeneveld 2003), suggesting no consistent difference in the response to treatment between these two groups. Using a Cox proportional hazards analysis that combined data from all five studies to estimate the hazard ratio for the interaction term (treatment x familial ALS) provides a means of directly addressing the question of whether treatment response differs between people with the familial and the sporadic form of ALS. The HR estimated using this approach was 0.90 suggesting a more beneficial response to treatment for people with fALS/MND, but the 95% confidence interval spans 1.0 (no difference) with a P value of 0.90.

In the second analysis using a linear mixed‐effects model with data pooled across the five studies, a pooled estimate of the difference in slopes (rate of decline of the ALSFRS) suggests a slightly better response to treatment in people with fALS/MND, but again the results were not significant with the 95% confidence intervals spanning 1.0.

From the available data, therefore, there is little evidence upon which to base a definitive answer to the question of whether there is a differential response to treatment among people with the familial and sporadic forms of ALS/MND.

Potential biases in the review process

In order to address the question posed by this systematic review it was necessary to contact the authors of all 93 published randomized controlled trials (RCT) for people with ALS/MND. This was a challenging undertaking given that these RCTs have been performed over a period that spans almost three decades. We were unable to obtain a response from the authors of 17 published studies, a significant number (n = 26) of studies deliberately excluded people with fALS/MND and a further 25, by chance, did not enroll any (or enrolled very few) people with the familial form of the disease. Data were either unavailable (n = 8) or the authors were unwilling to provide the raw data (n = 8) to permit the necessary analyses. Only five studies for which it was possible to obtain the raw data remained. This review, therefore, is hampered by significant missing data.

Agreements and disagreements with other studies or reviews

Although there are currently three ongoing trials restricted to people with fALS/MND, there are no published therapeutic trials that have been restricted to this population. Similarly, we are not aware of any attempts outside of this review to extract and synthesize data on participants with fALS from previously published trials that have focused predominantly on participants with sporadic ALS.

Authors' conclusions

Implications for practice.

There is insufficient evidence from available trials to decide whether or not there is a differential treatment response between familial and sporadic amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). In the absence of evidence for a differential treatment response, usual forms of treatment are warranted both for people with familial and sporadic forms of ALS/MND.

Implications for research.

The trend towards a slower rate of decline of the ALSFRS among people with familial ALS treated with arimoclomol is of considerable interest and warrants further investigation. The ongoing randomized, double‐blind, placebo‐controlled trial of arimoclomol in people with rapidly progressive familial ALS due to mutations in the SOD1 gene should illuminate this potentially interesting finding.

Future randomised controlled trials (RCTs) should clearly document (1) whether or not people with familial ALS are eligible for inclusion, (2) whether, and how many, participants with familial ALS are enrolled, and (3) whether participants with the familial form of ALS have mutations in an ALS susceptibility gene such as SOD1. ALS clinical trialists should search for an improved mechanism to permit sharing of data derived from RCTs. The availability of such data will permit an update of this review in the future and will perhaps permit a more robust answer to the question at hand.

What's new

Date	Event	Description
6 August 2010	New search has been performed	Searches updated to July 2010 and new trial added. Additional studies awaiting classification, pending contact with authors.

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History

Protocol first published: Issue 3, 2006  Review first published: Issue 1, 2009

Date	Event	Description
21 March 2008	Amended	Converted to new review format.
17 March 2006	New citation required and major changes	Substantive amendment

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Acknowledgements

The authors are grateful to Drs Merit Cudkowicz, Jeremy Shefner and Geeert Groeneveld for generously sharing the raw data from their RCTs. This review would not have been possible without their kind cooperation.

Appendices

Appendix 1. MEDLINE OvidSP search strategy

1 randomized controlled trial.pt.   2 controlled clinical trial.pt.   3 randomized.ab.   4 placebo.ab.   5 drug therapy.fs.   6 randomly.ab.   7 trial.ab.   8 groups.ab.   9 or/1‐8   10 exp animals/ not humans.sh.   11 9 not 10   12 exp Motor Neuron Disease/   13 (moto$1 neuron$1 disease$1 or moto?neuron$1 disease$1).mp.   14 Amyotrophic Lateral Sclerosis.mp.   15 (((Lou Gehrig$1 adj5 syndrome$1) or Lou Gehrig$1) adj5 disease$1).mp.   16 or/12‐15   17 11 and 16

Appendix 2. EMBASE OvidSP search strategy

1 crossover‐procedure/   2 double‐blind procedure/   3 randomized controlled trial/   4 single‐blind procedure/   5 (random$ or factorial$ or crossover$ or cross over$ or cross‐over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$ or allocat$ or volunteer$).tw.   6 or/1‐5   7 human/   8 6 and 7   9 nonhuman/ or human/   10 6 not 9   11 8 or 10   12 exp Motor Neuron Disease/   13 (moto$1 neuron$1 disease$1 or moto?neuron$1 disease$1).mp.   14 Amyotrophic Lateral Sclerosis.mp.   15 ((lou gehrig$1 adj5 syndrome$1) or (lou gehrig$1 adj5 disease$1)).mp.   16 or/12‐15   17 11 and 16

Appendix 3. Cochrane Central Register of Controlled Trials

#1MeSH descriptor Motor Neuron Disease explode all trees   #2"motor neuron disease" OR "motor neurone disease" OR "motoneuron disease" OR "motorneuron disease" OR "amyotrophic lateral sclerosis"   #3(Gehrig* NEAR syndrome*)   #4(Gehrig* NEAR disease*)   #5(#1 OR #2 OR #3 OR #4)

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Cudkowicz 2003.

Methods	Randomized, double‐blind, placebo‐controlled
Participants	United States N = 296 (topiramate ‐ 197, placebo ‐ 97) Mean age: 57.8 (topiramate), 57.7 (placebo) Gender distribution, male (%): 63.5% (topiramate), 66% (placebo) Family history of ALS: 3.1% (topiramate), 6.2% (placebo)
Interventions	Topiramate or placebo Maximum tolerated dose of a maximum of 800 mg/day
Outcomes	Primary: change in the rate of decline of the arm megascore, calculated based on the results on MVIC testing of 8 arm muscles (bilateral shoulder and elbow, flexion and extension) Secondary: forced vital capacity, ALSFRS, grip strength, survival (death or tracheostomy)
Notes	Support from National Institute of Neurological Disorders and Stroke (NINDS), Muscular Dystrophy Association (MDA), Ortho‐McNeil Pharmaceutical Inc. and General Clinical Research Centers
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer generated randomization
Allocation concealment?	Low risk	Coordination center staff, all site investigators, coordinators and the clinical evaluators were blind to treatment assignment throughout the study
Blinding?   All outcomes	Low risk	Coordination center staff, all site investigators, coordinators and the clinical evaluators were blind to treatment assignment throughout the study
Incomplete outcome data addressed?   All outcomes	Low risk	Based on the intention‐to‐treat principle, the data set for analysis included all randomized participants with the exception of two participants
Free of selective reporting?	Low risk	Results for all primary and secondary outcome measures reported (see Table 3 in original paper)
Free of other bias?	High risk	Relatively small number of familial ALS participants

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Cudkowicz 2006.

Methods	Randomized, double‐blind, placebo‐controlled trial
Participants	United States N = 300 (celecoxib ‐ 201, placebo ‐ 99) Mean age: 54.5 (celecoxib), 55 (placebo) Gender distribution, male (%): 64% (celecoxib), 67% (placebo) Family history of ALS: 4.5% (celecoxib), 10% (placebo)
Interventions	Celecoxib or placebo 800 mg/day, divided into 2 doses and taken orally
Outcomes	Primary: change in the rate of decline of maximum voluntary isometric contraction (MVIC) strength of 8 arm muscles (bilateral shoulder and elbow, flexion and extension) Secondary: rate of decline of MVIC in 10 leg muscle groups, grip strength, vital capacity, motor unit number estimation, revised ALS functional rating scale (ALSFRS‐R), cerebrospinal fluid prostaglandin‐E2 levels, safety and tolerability, survival (time to death, tracheostomy or permanent assisted ventilation)
Notes	Support from Pharmacia and Pfizer, the Muscular Dystrophy Association and General Clinical Research Centers
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer‐generated randomization
Allocation concealment?	Low risk	All site investigators, coordinators, clinical evaluators and staff of the coordination and data management center were blind to treatment assignment throughout the study
Blinding?   All outcomes	Low risk	All site investigators, coordinators, clinical evaluators and staff of the coordination and data management center were blind to treatment assignment throughout the study
Incomplete outcome data addressed?   All outcomes	Low risk	Based on the intention‐to‐treat principle, the data set for analysis included all randomized subjects
Free of selective reporting?	Low risk	Results for all primary and secondary outcome measures reported (see Tables 2 and 3 in original paper)
Free of other bias?	High risk	Relatively small number of familial ALS participants

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Cudkowicz 2008.

Methods	Randomized, double‐blind, placebo‐controlled trial
Participants	United States N = 84 (75mg/day ‐ 22, 150 mg/day ‐ 20, 300 mg/day ‐ 22, placebo ‐ 22) Mean age: 52.6 (75 mg/day), 53.6 (150 mg/day), 55.1 (300 mg/day), 49.9 (placebo) Gender distribution, male (%): 50% (75 mg/day), 55% (150 mg/day), 59% (300 mg/day), 77% (placebo) Family history of ALS: 11% (arimoclomol), 18% (placebo)
Interventions	Arimoclomol or placebo 75 mg, 150 mg or 300 mg/day, divided in three doses and taken orally
Outcomes	Safety: evaluated by assessment of vital signs, weight, body mass index, laboratory tests, ECGs, physical examination, reporting of adverse and serious adverse events, as well as rates of change of vital capacity and the ALSFRS‐R Tolerability: participants were regarded as treatment failure if they failed to complete week 12 of the study on the originally assigned treatment due to adverse events Pharmacokinetics: assessment of serum levels to determine Cmax, Tmax, area under the concentration curve and half‐life
Notes	Study support by CytRx Corporation and the National Center for Research Resources, NIH
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Randomization scheme was independently developed by the Biostatistics Center at MGH
Allocation concealment?	Low risk	All Coordination Center staff ... investigators, site coordinators and site clinical evaluators were blinded to treatment group assignment throughout the study
Blinding?   All outcomes	Low risk	All Coordination Center staff, participants, investigators, site coordinators, and site clinical evaluators were blinded to treatment group assignment throughout the study
Incomplete outcome data addressed?   All outcomes	Low risk	In accordance with the intention‐to‐treat principle, all randomized participants were included in the primary statistical analyses
Free of selective reporting?	Low risk	Safety data, tolerability data and pharmacokinetic data are all reported, as per the methods described in the manuscript
Free of other bias?	High risk	Relatively small number of familial ALS participants

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Groeneveld 2003.

Methods	Randomized, double‐blind, placebo‐controlled
Participants	The Netherlands N = 175 (creatine ‐ 88, placebo ‐ 87) Mean age: 57.1 (creatine), 58.4 (placebo) Gender distribution, male (%): 56% (creatine), 62% (placebo) Family history of ALS: 1.1% (creatine), 6.9% (placebo)
Interventions	Creatine or placebo (Polycose, an odorless glucose polymer) 5 g twice daily
Outcomes	Primary: event‐free survival, where 'events' included death from any cause, tracheostomy and persistent assisted ventilation Secondary: rate of decline of MVCI strength of 8 muscle groups in the arms (bilateral shoulder and elbow, flexion and extension), rate of decline of vital capacity, rate of decline of ALSFRS‐R, physical and mental summary scores of the Short Form‐36 (SF‐36)
Notes	Support from the Dammers Fonds, the ALS Onderzoeksfonds and the Royal Netherlands Academy of Arts and Sciences
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Randomization was performed by an independent physician according to the minimization method of Pocock and Zelen
Allocation concealment?	Low risk	After having allocated a trial participant to 1 of 2 treatment groups, Groups A or B, the independent physician, ignorant to whether A or B was creatine, would instruct the research pharmacist to prepare trial medication A or B. The research pharmacist was the only person who knew the trial code of A or B
Blinding?   All outcomes	Low risk	"... to receive creatine monohydrate ... or the same dose of Polycose, an odorless glucose polymer resembling creatine monohydrate in color and form" Trial medication was packed in blank containers and handed out at the coordinating site to the trial nurse, who delivered the trial medication to the participants
Incomplete outcome data addressed?   All outcomes	Low risk	The final analysis included the results of all 175 participants
Free of selective reporting?	Low risk	Results for all primary and secondary outcome measures reported
Free of other bias?	High risk	Small number of familial ALS participants

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Shefner 2004.

Methods	Randomized, double‐blind, placebo‐controlled
Participants	United States N = 104 (creatine ‐ 50, placebo ‐ 54) Mean age: 59 (creatine), 59 (placebo) Gender distribution, male (%): 66% (creatine), 57.4% (placebo) Family history of ALS: 2% (creatine), 5.6% (placebo)
Interventions	Creatine or placebo 20 g per day for 5 days, followed by 5 g per day
Outcomes	Primary: rate of decline of MVIC strength of 8 muscle groups in the arms (bilateral shoulder and elbow flexion and extension) Secondary: rate of decline of forced vital capacity, rate of decline of ALSFRS‐R, grip strength and motor unit number estimation (statistical technique)
Notes	The Muscular Dystrophy Association, the ALS Hope Foundation and Avicena Pharmaceuticals
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Randomization accomplished using a random number generator at the coordination center
Allocation concealment?	Low risk	The coordination center staff, all site investigators, coordinators and clinical evaluators, were blind to treatment assignment throughout the study
Blinding?   All outcomes	Low risk	Matching placebo The coordination center staff, all site investigators, coordinators and clinical evaluators, were blind to treatment assignment throughout the study
Incomplete outcome data addressed?   All outcomes	Low risk	Results for all primary and secondary outcome measures reported
Free of selective reporting?	Low risk	Based on the intention‐to‐treat principle, the data set for analysis included all randomized subjects
Free of other bias?	High risk	Small number of familial ALS participants

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ALS = amyotrophic lateral sclerosis   ALSFRS = ALS Functional Rating Scale   ECG = electrocardiogram   MVIC = maximum voluntary isometric contraction

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Appel 1988	People with familial ALS excluded
Askmark 1993	People with familial ALS excluded
Beghi 1993	People with familial ALS excluded
Beghi 2000	People with familial ALS excluded
Bello‐Haas 2007	Small number of people with familial ALS (N < 4)
Bensimon 1994	Refused to provide data
Bensimon 2002	Refused to provide data
Berto 2007	No people with familial ALS included
Blin 1992	No response to repeated requests for data
Blin 1996	No response to repeated requests for data
Borasio 1998	People with familial ALS excluded
Bourke 2006	Small number of participants with familial ALS (N < 4)
Bradley 1984	Data unavailable
Brody 1974	People with familial ALS excluded
Brooke 1986	Data unavailable
Brooks 1985	No response to repeated requests for data
Brooks 1996	Small number of participants with familial ALS (N < 4)
Caroscio 1986	No participants with familial ALS included
Chio 1998	People with familial ALS excluded
Desnuelle 2001	No response to repeated requests for data
Drachman 1994	No participants with familial ALS included
Drory 2001	Data unavailable
Eisen 1993	People with familial ALS excluded
Farkkila 1996	People with familial ALS excluded
Fornai 2008	No participants with familial ALS included
Goonetilleke 1995	No response to repeated requests for data
Gordon 2006	People with familial ALS excluded
Gordon 2007	People with familial ALS excluded
Gordon 2008	Small number of participants with familial ALS (N < 4)
Graf 2005	Refused to provide data
Gredal 1997	People with familial ALS excluded
Guiloff 1987	No participants with familial ALS included
Harrington 1984	No response to repeated requests for data
Hesselmans 1993	Data unavailable
Imoto 1984	No participants with familial ALS included
Janik 1996	People with familial ALS excluded
Jossan 1994	Data unavailable
Kasarskis 1999	Refused to provide data
Kaufmann 2008	Familial versus sporadic status not tracked
Kodama 2000	No people with familial ALS included
Kwiecinski 2001	People with familial ALS excluded
Lacomblez 1996	Refused to provide data
Lacomblez 1996a	Refused to provide data
Lacomblez 2004	Refused to provide data
Lai 1997	People with familial ALS excluded
Lange 1996	People with familial ALS excluded
Lange 1998	No response to repeated requests for data
Lauria 2009	People with familial ALS excluded
Lomen‐Hoerth 2007	No participants with familial ALS included
Louwerse 1995	People with familial ALS excluded
Mazzini 1994	People with familial ALS excluded
Meininger 2004	Refused to provide data
Meininger 2006	Small number of participants with familial ALS (N < 4)
Meyer 2008	No participants with familial ALS included
Miller 1994	People with familial ALS excluded
Miller 1996	People with familial ALS excluded
Miller 1996a	No participants with familial ALS included
Miller 2001	No participants with familial ALS included
Miller 2007	Familial versus sporadic status not tracked
Mitsumoto 1986	No participants with familial ALS included
Munsat 1992	No response to repeated requests for data
Murphy 1995	People with familial ALS excluded
Nagano 2005	No response to repeated requests for data
Nefussy 2010	People with familial ALS excluded
Norris 1974	People with familial ALS excluded
Norris 1986	People with familial ALS excluded
Norris 1993	People with familial ALS excluded
Ochs 2000	No participants with familial ALS included
Olarte 1979	No response to repeated requests for data
Olarte 1985	No response to repeated requests for data
Olson 1978	No participants with familial ALS included
Palma 2000	No response to repeated requests for data
Pascuzzi 2010	Small number of participants with familial ALS included (N < 4)
Piepers 2008	Small number of participants with familial ALS included (N < 4)
Piepers 2009	Small number of participants with familial ALS included (N < 4)
Plaitakis 1988	No response to repeated requests for data
Pontieri 2005	No participants with familial ALS included
Rivera 1980	Data unavailable
Rosenfeld 2008	Familial versus sporadic status not tracked
Ryberg 2003	No response to repeated requests for data
Scelsa 2005	Small number of participants with familial ALS included (N < 4)
Smith 1993	Data unavailable
Smith 1994	People with familial ALS excluded
Sorenson 2008	Familial versus sporadic status not tracked
Steele 2007	Small number of participants with familial ALS (N < 4)
Stommel 2009	Small number of participants with familial ALS included (N < 4)
Szczudlik 1998	No response to repeated requests for data
Tandan 1996	No people with familial ALS included
Testa 1989	Small number of participants with familial ALS included (N < 4)
Testa 1992	Data unavailable
Tyler 1979	No response to repeated requests for data
Yanagisawa 1997	No response from translator regarding inclusion of participants with familial ALS
Ziv 1994	People with familial ALS excluded

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ALS = amyotrophic lateral sclerosis

Characteristics of studies awaiting assessment [ordered by study ID]

Aggarwal 2010.

Methods	Randomized, double‐blind, placebo‐controlled
Participants	United States and Canada N = 84 (lithium: 40, placebo: 44) Mean age 58.3 years (lithium), 55.5 years (placebo) Gender distribution, male (%): 75% (lithium), 55% (placebo) Family history of ALS: 8% (lithium), 2% (placebo)
Interventions	Lithium or placebo Lithium titrated to achieve serum concentration in the range of 0.4 to 0.8 mEq/l
Outcomes	Primary: time to event, defined as a decrease of at least 6 points from baseline on ALSFRS‐R or death Secondary: changes in the ALSRFS‐R, slow vital capacity, ALSSQOL and QIDS‐SR₁₆
Notes	Support from the National Institute of Neurological Disorders and Stroke, the ALS Association and the ALS Society of Canada

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Cudkowicz 2009.

Methods	Open‐label dose‐escalation study
Participants	United States N = 40 Mean age 59.1 years Gender distribution, male (%): 85% Family history of ALS: not reported in published manuscript
Interventions	Sodium phenylbutyrate 21 g/day or maximum tolerated dose
Outcomes	Primary: tolerability Secondary: safety, sodium phenylbutyrate metabolite blood levels, riluzole levels and histone acetylation activity levels
Notes	Support from the Department of Veterans Affairs and the Muscular Dystrophy Association

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Di Lazzaro V 2009.

Methods	Randomized, double‐blind, placebo‐controlled
Participants	United States N = 20 Mean age 60.2 years (rTMS), 55.1 years (sham) Gender distribution, male (%): 80% (rTMS), 70% (sham) Family history of ALS: not reported in published manuscript
Interventions	Repetitive transcranial magnetic stimulation (rTMS) given as continuous theta burst stimulation (cTBS) monthly for 1 year or sham rTMS
Outcomes	Primary: rate of decline of ALSFRS‐R Secondary: rate of decline in strength (measured using manual muscle testing) and peripheral brain derived neurotrophic factor (BDNF) production
Notes	Funded by the Ministero della Salute

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Kaufmann 2009.

Methods	Two‐stage, adaptive‐design, randomized, placebo‐controlled, double‐blind
Participants	United States Stage 1: N = 105 (CoQ10 1800 mg: 35, CoQ10 2700 mg: 35, placebo: 35) Stage 1: mean age 59.4 years (CoQ10 1800 mg), 56.1 years (CoQ10 2700 mg) Stage 1: gender distribution, male (%): 71.4% (CoQ10 1800 mg), 42.9% (CoQ10 2700 mg) Stage 1: family history of ALS not reported in published manuscript Stage 2: N = 150 (75 CoQ10 2700 mg (including 35 who received CoQ10 2700 mg in stage 1) and 75 placebo (including 35 who received placebo in stage 1)) Stage 2: mean age 56.5 years (CoQ10), 57.4 years (placebo) Stage 2: gender distribution, male (%): 53.3% (CoQ10), 61.3% (placebo) Stage 2: family history of ALS not reported in published manuscript
Interventions	Coenzyme Q10 Stage 1: 1800 mg/day, 2700 mg/day Stage 2: 2700 mg/day
Outcomes	Primary: decline in the ALSFRS‐R
Notes	Funded by the National Institute of Neurological Disorders and Stroke

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Meininger 2009.

Methods	Randomized, double‐blind, placebo‐controlled
Participants	Six countries in Europe N = 366 (glatiramer acetate: 184, placebo: 182) Mean age 55.7 years (glatiramer acetate), 56.7 years (placebo) Gender distribution, male (%): 62.5% (glatiramer acetate), 60.4% (placebo) Family history of ALS not reported in published manuscript
Interventions	Glatiramer acetate 40 mg subcutaneously x 52 weeks
Outcomes	Primary: slope of the ALSFRS‐R Secondary: time to death, tracheostomy or permanent assisted ventilation
Notes	Funded by Teva Pharmaceutical Industries

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Parry 2010.

Methods	Randomized, dose‐escalation
Participants	United States N = 18 (15 mg/day: 7, 30 mg/day: 4, 50 mg/day: 7) Mean age 48.9 years (15 mg/d), 58.3 years (30 mg/d), 56.6 years (50 mg/d) Gender distribution, male (%): 57.1% (15 mg/d), 50% (30 mg/d), 57.1% (50 mg/d) Family history of ALS not reported in published manuscript
Interventions	Ursodeocycholic acid 15 mg/day, 30 mg/day and 50 mg/day
Outcomes	Primary: safety and tolerability
Notes	Funded by Axcan Pharma Inc.

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Sacca 2009.

Methods	Randomized, double‐blind, placebo‐controlled
Participants	Italy N = 45 (distribution of subjects between growth hormone and placebo groups not described in published abstract) Mean age not reported in abstract Gender distribution, male (%), 64.4% Family history of ALS not reported in published abstract
Interventions	Growth hormone 2U subcutaneous every other day; dose titration to reach 1.5, which is 2 x upper limit of normal IGF‐1 levels
Outcomes	Primary: N‐acetylaspartate/creatine + choline ratio in the motor cortex Secondary: mortality, ALSFRS‐R and SF‐36 scores
Notes	Funded by Agenzia Italiana del Farmaco

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Zanette 2008.

Methods	Randomized, controlled
Participants	Italy N = 10 (5 rTMS, 5 sham) Mean age 59.4 years (rTMS), 60.2 years (sham) Gender distribution, male (%): 80% (rTMS), 60% (sham) Family history of ALS not reported in published manuscript
Interventions	Repetitive transcranial magnetic stimulation (rTMS) given at 5 Hz
Outcomes	Disease progression: decline of ALSFRS‐R Fatigue: Fatigue Severity Scale Quality of life: Short‐Form 36 (SF‐36) Muscle strength: Medical Research Council Scale, maximum voluntary isometric contraction
Notes	Funding sources not specified

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ALS = amyotrophic lateral sclerosis   ALSFRS = Amyotrophic Lateral Sclerosis Functional Rating Scale   CoQ10 = coenzyme Q10   ALSSQOL = ALS‐Specific Quality of Life Instrument   QIDS‐SR₁₆ = Quick Index of Depressive Symptomatology (Self‐Report)   rTMS = repetitive transcranial magnetic stimulation   IGF‐1 = insulin‐like growth factor‐1

Differences between protocol and review

The analyses presented here differ from those proposed in the original protocol for this review. In the original protocol we proposed methods for comparing survival proportions at 12 months post randomization. This turned out to be impractical for two reasons: participants dropped out prior to 12 months and there were no deaths in some treatment arms during the course of the study. Thus, we elected to use a Cox proportional hazards model with an interaction term specifically to test whether there were treatment effect differences due to ALS type. This is a more efficient way to analyze the data. For secondary, continuous valued measurements decreasing values over time made it difficult to compare means so we elected to compare slopes (rates of decline over time) using a linear mixed‐effects model with an interaction term for effect x ALS type. Again, this was a more efficient use of the data.

The protocol also proposed analyses of the secondary outcomes of forced vital capacity and muscle strength but these analyses were not carried out since there were no data for them in some of the studies. The resulting reduced sample sizes plus the inherently greater within‐patient variability of these measures compared to the ALS Functional Rating Scale (ALSFRS) led to our decision to only include ALSFRS as a secondary outcome measure.

Contributions of authors

Michael Benatar wrote the first draft of the protocol. Dan Moore compiled the data analysis plan. Together Michael Benatar and Dan Moore modified the protocol in response to reviewers’ comments. Jerome Kurent reviewed and commented on the original and revised protocol. Michael Benatar and Jerome Kurent independently each reviewed all manuscripts, abstracted data and discussed each manuscript to determine appropriateness for inclusion in this review. Dan Moore performed the data analysis. Michael Benatar wrote the first draft of the full review. Dan Moore and Jerome Kurent provided comments and edits and approved the final draft of the review which was written by Michael Benatar. Michael Benatar and Jerome Kurent reviewed all manuscripts for the update and independently abstracted data. Dan Moore revised and updated the analysis. Michael Benatar modified the review to incorporate the newly identified studies and Dan Moore critically reviewed the revised manuscript.

Declarations of interest

Michael Benatar is the principal investigator of the ongoing randomized, double‐blind, placebo‐controlled of arimoclomol in SOD1 positive familial ALS. This trial is jointly funded by the ALS Association and the Food & Drug Administration.

New search for studies and content updated (no change to conclusions)

References

References to studies included in this review

Cudkowicz 2003 {published and unpublished data}

Cudkowicz ME, Shefner JM, Schoenfeld DA, Brown RH Jr, Johnson H, Qureshi M, et al. A randomized, placebo‐controlled trial of topiramate in amyotrophic lateral sclerosis [see comment]. Neurology 2003;61(4):456‐64. [PUBMED: 12939417] [DOI] [PubMed] [Google Scholar]

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Appel 1988 {published data only}

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References to studies awaiting assessment

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PERMALINK

Treatment for familial amyotrophic lateral sclerosis/motor neuron disease

Michael Benatar

Jerome Kurent

Dan H Moore

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selecting trials for inclusion

Assessment of methodological quality

Data extraction

Analysis

Results

Description of studies

Results of the search

Included studies

Excluded studies

Studies awaiting classification

Risk of bias in included studies

1.

Effects of interventions

1. Study distribution of sporadic and familial cases.

2. Distribution of people with ALS by study, treatment group, ALS genotype and survival status.

3. Hazard ratio estimates by study (95% confidence intervals).

4. Cox proportional hazards results.

5. Estimates of slopes from linear mixed‐effects model 1.

Discussion

Summary of main results

Potential biases in the review process

Agreements and disagreements with other studies or reviews

Authors' conclusions

Implications for practice.

Implications for research.

What's new

History

Acknowledgements

Appendices

Appendix 1. MEDLINE OvidSP search strategy

Appendix 2. EMBASE OvidSP search strategy

Appendix 3. Cochrane Central Register of Controlled Trials

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Cudkowicz 2003.

Cudkowicz 2006.

Cudkowicz 2008.

Groeneveld 2003.

Shefner 2004.

Characteristics of excluded studies [ordered by study ID]

Characteristics of studies awaiting assessment [ordered by study ID]

Aggarwal 2010.

Cudkowicz 2009.

Di Lazzaro V 2009.

Kaufmann 2009.

Meininger 2009.

Parry 2010.

Sacca 2009.

Zanette 2008.

Differences between protocol and review

Contributions of authors

Declarations of interest

5. Estimates of slopes from linear mixed‐effects model ¹.