Neuromuscular Disorders 17 (2007) 499–505 www.elsevier.com/locate/nmd Meeting report Issues in SMA clinical trial design The International Coordinating Committee (ICC) for SMA Subcommittee on SMA Clinical Trial Design
P. Kaufmann a,*, F. Muntoni b
a Department of Neurology, Columbia University, New York, USA b Hammersmith Hospital, Imperial College, London, UK
1. Introduction intended to modulate the SMN2 gene transcription or splicing should be tested in animal models carrying Advances in preclinical SMA research have identified the human version of the SMN2 gene (including its several candidate treatments. Early clinical trials evaluat- regulatory elements). For these presumed SMN2 mod- ing these medications are underway or in the planning ulators, markers of bioactivity include full length stage. SMN transcript or protein (Western blot and immu- At the NINDS Workshop on SMA in September nohistochemistry) in different tissues including the 2004 in Washington DC, discussions started within the spinal cord. The pharmacokinetics need to be taken international SMA community to identify features that into account when planning study time points relative should be common to SMA clinical trials [1]. to drug administration. However, it is possible that Having a set of design features and outcome mea- drugs may improve function or increase survival with- sures common to clinical trials would allow for out measurably increasing SMN2 mRNA or protein levels. Independent of presumed drug mechanism, • Comparison of data across trials. the following outcomes should be considered in ani- • Establishment of a data repository with placebo mal testing: survival, motor function, body weight, group data (for planning of future trials). motor unit number estimation, and histopathological • Rapid expansion to additional sites in future Phase findings related to motor unit loss. While animal mod- III trials (because sites will have experience with com- els can be very helpful in assessing candidates, lack of parable outcome measures and procedures). an effect in a given SMA animal model should not be used to exclude a promising candidate in the presence Because early clinical trials are already underway or of other data supporting potential therapeutic benefit. in the planning phase (in the USA and Europe), it is An extensive clinical trials experience in other neuro- important that the different groups reach consensus on degenerative diseases, including ALS, has taught us a core set of data elements and design features that important lessons about the benefits and drawbacks would be common to all SMA trials. of animal models in translating treatments to human trials [2]. 2. Criteria to move drugs from preclinical or animal testing into human trials 3. Shared database for SMA clinical research
The efficacy of experimental treatments should be The natural history of SMA is evolving. Function evaluated in animal models when possible. Drugs and life expectancy have improved with advances in * Corresponding author. medical and, in particular, respiratory care, and the E-mail address: [email protected] (P. Kaufmann). effect of these interventions is particular evident in
0960-8966/$ - see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2006.12.001 500 P. Kaufmann, F. Muntoni / Neuromuscular Disorders 17 (2007) 499–505 patients at the severe end of the clinical spectrum. We 5. Placebo controlled trials have relatively limited composite data on the natural history of SMA using comparable clinical outcome mea- The evaluation of new treatments for safety and sures, and more information is needed to improve the efficacy requires prospective randomized, placebo- planning of SMA clinical trials. This information could controlled clinical trials. Placebo controlled, dou- be collected in a repository for data from natural history ble-blind trials can reduce bias when efficacy is studies, clinical trial placebo groups, and data from neg- studied. Open label designs can falsely suggest effi- ative clinical trials. Data collected could include longitu- cacy and fail to uncover harmful effects. Placebo dinal observations of motor function, pulmonary controlled trials are considered ethical when there function, and muscle strength. For use in planning or is no standard treatment better than placebo, and conducting clinical trials, it is most helpful if relevant when participants are informed about the use of a data are systematically collected by well-trained person- placebo [5]. In Amyotrophic Lateral Sclerosis, a nel using standardized procedures (e.g. comparable out- severe and progressive motor neuron disease mainly comes, measurement procedures, visit intervals, and affecting adults, placebo controlled trials have been observation period). feasible and have resulted in drug approval [6–8]. The FDA has published suggested data elements for The FDA Division for Neurological Drug Products clinical datasets [3]. For potential data use in the reg- has not approved a new drug without a controlled ulatory approval process, detailed safety data are trial. needed in addition to outcome data. These data should best be coded using one of the standard coding schemes (e.g., CTCAE [4]). Establishing a data ware- 6. Collaboration between patient advocates and house will require funding for data management and researchers during planning and implementation of statistical support, a steering committee that can over- clinical trials see criteria for submission of data to the data ware- house and the dissemination of the data to SMA Successful clinical trials require timely recruitment. investigators. A data warehouse for SMA could be A scientifically well designed trial is not feasible if established independently or linked to an already exist- patients are reluctant to enroll. SMA researchers and ing database. families have the same goal: finding an effective treat- ment for SMA as soon as possible. This goal could 4. Biomaterial and cell line banking be achieved sooner if most patients with SMA partici- pated in clinical trials. Patient advocacy groups can If there were centralized biomaterial repositories, help investigators design trials that are likely accept- investigators could submit samples of SMA patients able to patients. Researchers and patient advocates (collected from clinical trials placebo and treated can work together in educating patients on the necessi- groups). These samples would be useful to discover ty of clinical trials. Education may occur by word of and to validate new biomarkers of disease progression, mouth, publications and websites, or during support investigate modifying genes, study pharmacogenomic groups or family meetings. The following should be aspects, and to address future research questions. Multi- considered when planning trials and communicating center studies will likely require more than one with families: repository given limitations in shipping samples, espe- cially for protein assays and cell cultures. It will be • Centers participating in clinical trials will strive to important to have uniform specimen collection and provide expert care for SMA patients. processing as well as standardized assays between • Careful safety monitoring during a clinical trial helps sites. Also, any tissue and cell repository would be to protect participants from possible adverse effects enhanced if it was based on a phenotypically well of new treatments. described patient group and if the samples could be • Other disease communities (e.g., AIDS, pediatric linked to a database of uniformly collected clinical oncology, ALS) have found successful treatments information. by endorsing placebo-controlled clinical trials (after The investigation of tissue samples from autopsies some initial resistance). might help progress in laboratory research. Even though • There are multiple examples of new treatments that this is a sensitive subject, it might be in the interest of the were actually found to be harmful in clinical trials. SMA community to consider asking research partici- Many more patients might have been exposed if these pants for post-mortem donations. This would allow harmful effects had not been identified in clinical research investigations that cannot be performed in trials [9,10]. blood samples alone (e.g., histological study of motor • Physicians choose participation in clinical trials when units in the spinal cord). they are in the patient role [11]. P. Kaufmann, F. Muntoni / Neuromuscular Disorders 17 (2007) 499–505 501
7. Recruitment and retention Two- or multi-stage designs allow for analysis at different stages of the trial and thus for early termi- Recruitment and retention in clinical trials may be nation if the treatment appears ineffective. Generally, facilitated by increasing the number of patients receiv- they would not allow early termination for efficacy ing active treatment (for example, 2:1 randomization). [17,18]. They can increase efficiency in Phase II drug Trial designs that include interim analyses with the development because they may result in declaring intent to make a new treatment available to all, if futility at an earlier point during the trial when fewer effective, as early as possible may enhance recruitment patients have been exposed. and retention. Similarly, trial designs that would Information gained from exposure of patients in uncover futility as early as possible would likely be Phase II studies may not always be optimally used when more acceptable to families because they would mini- drug development follows the discrete steps of conven- mize the exposure time to treatments deemed not tional Phase II and Phase III trials. Treatment is discon- effective. tinued at the end of the Phase II follow-up period so To facilitate recruitment and retention, the visit that the opportunity to obtain longer-term exposure schedule and study duration have to be acceptable to data is lost. In addition, there is typically a time lapse families. The tests planned for each visit cannot be too of several months between a completed Phase II trial taxing for the participant. and start-up of the subsequent Phase III trial due to funding, regulatory and other issues. Adaptive, seamless 8. Trial design issues in SMA designs can reduce delays and increase efficiency in time as well as sample size. These are designs that allow par- For new compounds with limited data on use in ticipants to seamlessly roll over into the next phase of humans the drug regulatory agencies require Phase I the trial, for example from a preliminary Phase II effica- testing. For compounds approved for indications other cy test into a Phase III trial. However, seamless Phase than SMA, limited Phase I testing may also be needed II/III trials are often logistically complex. Also, regula- to determine the dose, pharmacokinetics and prelimin- tory approval may be easier when a trial is planned in ary safety in the targeted population. Trial designs are two separate steps with data from phase II available typically dose escalation studies using fixed cohort size by the time of phase III approval. Conducting efficacy or adaptive designs [12–14] (e.g., continual-reassessment trials in a rare disease is challenging. However, there is designs), and/or pharmacokinetic studies. precedent for relatively small efficacy trials leading to Phase II studies, usually examine one or multiple regulatory approval in orphan diseases (e.g., alpha dosages in terms of safety, tolerability, and prelimin- glucosidase in Pompe disease [19]). ary drug activity prior to exposing a larger number Phase III studies evaluating efficacy and longer-term of patients to the new treatment in Phase III. Also, safety are needed before a medication is approved and given the finite number of patients in a relatively rare recommended for the treatment of SMA patients. Phase disease such as SMA, and given the limited resources, III studies test the null hypothesis that the new treat- Phase II trials can help in selecting the most promis- ment and placebo are equal, controlling the error of ing candidate among multiple drugs for a future Phase falsely declaring a new drug efficacious. Phase III studies III trial. are typically large and will require a multi-center and Phase II studies can include ranking and selection possibly international effort. methods. Other than in formal hypothesis tests, in selec- Phase III trials should be randomized, double-blind, tion and ranking procedures the interest is not in guard- and placebo-controlled, and all should require the pri- ing against commission of a type I error under the mary statistical analysis to be performed according to assumption of equal efficacy; rather, interest resides in the intention-to-treat principle. An unbalanced random- making a required selection between drugs to move for- ization scheme (2:1 active to placebo) can be considered ward to efficacy testing [15]. These are typically more to facilitate recruitment. In trials with a reasonably efficient in terms of sample size than hypothesis testing. short follow-up period, or a time-to-event outcome, Ranking and selection procedures are strategically group sequential or fully sequential designs can similarly important at a time when multiple treatments that have be more efficient than designs requiring a fixed sample shown promise in vivo are awaiting clinical testing. size. Sequential designs aim to limit the number of sub- Other trial designs that can increase the efficiency of jects in a trial once there is sufficient evidence of superi- Phase II trials include non-superiority or futility studies ority or futility and have been used in motor neuron [16]. Here, the error of declaring a new drug as ineffec- disease trials [20,21]. Cross-over designs can increase tive is controlled by reversing the null and alternative efficiency in Phase III but have several limitations hypotheses compared to a conventional Phase III including the possibilities of a non-linear disease course, design. The sample size can thus be relatively smaller or carry-over of drug effects. Factorial designs can compared to a conventional Phase III trial. increase the proportion of subjects randomized to one 502 P. Kaufmann, F. Muntoni / Neuromuscular Disorders 17 (2007) 499–505 of the active treatments and accelerate the testing of 10. Phase III trial design issues for SMA Type 1 more than one experimental compound. 10.1. Study population 9. Study population A fairly wide clinical spectrum is included under Type To be inclusive, individuals across the spectrum of 1 (sometimes termed Types 1a, b, c), with differences in disease severity and age should be offered clinical trials age at onset and prognosis, although the neonatal onset participation when possible. Studies involving patients (1a) and the mildest form (1c, closer to Type II SMA) with Type 1, Type 2 or Type 3 SMA can be carried are less common than the typical SMA Type I (1b). A out in parallel. However, different trial designs may be decimal classification ranging from SMA 1.0 to 1.9 has necessary for each of these different entities. been suggested for SMA1, and, similarly, for the milder Inclusion criteria should be simple and allow as SMA variants [22]. The SMA Type 1 study population broad a patient group as possible to participate while may need to be further defined or stratified, for example maintaining the trial’s scientific integrity. Complicated by age at onset and/or SMN2 copy number. While and overly restrictive criteria can impede recruitment. inclusiveness is important, it is currently difficult to The inclusion criteria define the age range and dis- design a trial targeting the most severe end of the clinical ease stage of the targeted population and will depend spectrum, in particular neonatal onset SMA. If universal on the age range for which the outcome measures newborn screening for SMA was instituted, then clinical can be reliably administered, and on the presumed trials for the most severely affected type 1 patients as mechanism and safety profile of the study well as pre-symptomatic treatment for other patients intervention. could be considered. The SMA phenotypes are primarily clinically defined based on the highest motor function ever achieved (i.e. 10.2. Outcome measures never sat = Type 1, ever sat = Type 2, ever walked = Type 3). SMN2 copy number may be used to determine 10.2.1. Primary outcome measures inclusion based on the association between clinical pheno- Survival time (from randomization) or the time to an type and SMN2 copy number. However, this associa- equivalent respiratory outcome is a possible primary tion is not perfect. If SMN2 copy number is needed as endpoint for an SMA type 1 clinical trial. The definition inclusion criterion (such as in young SMA 1 patients), of respiratory insufficiency that would be equivalent to a copy number assays have to be available reliably and survival endpoint requires agreement on a specific defi- with reasonable short turnaround time. Exclusion crite- nition. Respiratory insufficiency is generally defined as ria should be carefully considered and justified by the inability to maintain adequate alveolar ventilation patient safety considerations. Patient advocates ask that and gas exchange. SMA patients typically present with we exclude as few patients as possible from the opportu- an acute deterioration of underlying chronic respiratory nity of participating in a clinical trial. For example, one compromise (respiratory muscle weakness, ventilatory should carefully consider excluding SMA 2 patients who restriction, insufficient cough). Factors other than dis- had spinal fusion surgery in the past, even if the surgery ease progression may influence the time point when limits the performance range on motor function respiratory insufficiency occurs (e.g., seasonal differences measures. in the incidence of respiratory infections, use of preven- Medical care, including nutritional and respiratory tative measures such as influenza vaccine and RSV pro- interventions, influences prognosis and should be stan- phylaxis). To account for acute, temporary worsening in dardized when possible. Uniform standards of care the setting of infection, a respiratory insufficiency end- would be expected to reduce variability between subjects point could be further described by its persistence. How- and thus possibly reduce the sample size required for ever, including persistence in the definition of an studies. However, cultural circumstances and parent endpoint can introduce uncertainty and needs waiting choices have impact on management and prognosis time before the outcome can be ascertained. and cannot be equalized. The likelihood that differences In clinical trials for Amyotrophic Lateral Sclerosis in care between sites will affect results of a randomized (ALS), investigators have chosen as respiratory end- trial can be minimized when randomization is stratified point the time when more than 18 hours of mechanical by site. Also, a trial that does not attempt to strictly ventilation were needed. When considering a similar ‘‘regulate’’ standard of care is closer to the reality of endpoint for SMA, it will have to be defined such that SMA patients, more feasible and will have results that a sufficient proportion of the study population reaches are more applicable to the general SMA population. the endpoint during the trial period. Also, respiratory Any intervention or treatment that is medically indicat- status and interventions are influenced by the pulmon- ed during the follow-up period should not be prevented ary care provided with practices varying between sites, by the patient’s clinical trial participation. including the use of partial diurnal ventilatory support. P. Kaufmann, F. Muntoni / Neuromuscular Disorders 17 (2007) 499–505 503
In addition to chronic diurnal respiratory insufficien- 10.3. Duration of follow-up period and frequency of visits cy, symptomatic nocturnal hypoventilation should be considered [23]. This is important because the use of The duration for a study in Type 1 SMA will depend non-invasive nocturnal ventilation in patients with on the event rates. However, any placebo controlled chronic nocturnal hypoventilation may delay the onset study of long duration may not be easily acceptable to of diurnal respiratory failure. families. The visit schedule has to be acceptable to fam- The definition of a respiratory endpoint has to care- ilies and the evaluations at a given visit have to be fully balance the need to have a clinical trial endpoint planned with consideration to patient and family that can be reliably and feasibly ascertained against burden. the need to have a clinically meaningful pulmonary mea- sure. The specific definition will depend on the study 11. Trial design issues for SMA Types 2 and 3 population targeted in a given trial. 11.1. Study population 10.2.2. Secondary outcome measures Possible secondary outcome measures are respiratory Inclusion criteria require a specific clinical definition measures, motor function measures, electrophysiologi- for the SMA phenotype (SMA Type 2 may be defined cal measures (including motor unit number estimation by the subject’s ability to ever have sat independently – MUNE), and biological markers of SMN gene for at least 30 s when placed. SMA Type 3 may be defined expression. by the subject’s ability to ever walk 4 steps unassisted). As Establishing reliable infant motor function measures with type I, type III can be divided into IIIa (diagnosed by for SMA 1 is complex because the measures have to age 3 years) and IIIb (diagnosed over age 3 years). These account for developmental maturation, the level of groups have been shown to have different natural history cooperation and other confounding factors. as to age when independent ambulation is lost. Pulmonary function testing in infants and young chil- One or more of these phenotypic groups may be dren is limited by their inability to fully cooperate. Pulse included in a given trial. Additional age limitations to oxymetry and end-tidal carbon dioxide measurements the study population will likely be determined by choice are feasible and reproducible in young children and of outcome measure (for example, some motor function reflect the effectiveness of alveolar ventilation. Respira- measures may require a minimum age of 30 months, and tory outcomes can include the frequency of respiratory most respiratory measures or muscle strength measures infections with hospital admission and/or hypoxemia, may require a minimum age of 5 years). the presence of daytime hypercapnia, or presence of noc- turnal hypoventilation (for example, mean, nadir, and 11.2. Outcome measures percent of sleep time with oxygen saturations below 90% and/or mean, maximum, and percent of sleep time The primary outcome may be the change from base- with carbon dioxide tensions above 50 mmHg). line to end-of-study in a motor function measure, respi- Motor unit number estimation (MUNE) is a quantita- ratory measure, strength measure or other functional tive assessment of the number of functional motor units measure. Given that most patients are in a phase of rel- and thus relevant to the disease process underlying ative clinical stability at the time of trial entry, studies SMA. It is feasible in infants and children with SMA, will likely be designed to demonstrate improved muscle correlates with the clinical severity, and can demonstrate strength or function rather than slowing of disease pro- a decline in motor units before clinical symptoms or gression [27]. However, disease progression may be not- signs emerge [24–26]. ed over longer observation periods [28]. Biological outcome measures might include the level Motor function measures used in SMA include the of full length SMN transcript or protein and should be Gross Motor Function Measure (GMFM), a non-dis- evaluated prior to the first dose and at different intervals ease specific measure. It has been validated in SMA relative from the dose (interval depends on the pharma- [29,30], but can take more than 30 minutes to be com- cokinetics of the study drug). Additional biological mea- pleted. The Hammersmith motor function scale for sures that have been proposed by laboratory researchers SMA is an alternative motor function measure and is (e.g., 3-2 snRNP assembly in leukocytes) or other future disease specific [31,32]. The Hammersmith measure is biomarkers might be included in a trial. This will allow shorter and easier to administer, but may be limited to comparing the sensitivity of new tests with more estab- a moderate phenotype within the SMA Type 2 spectrum lished methods (such as western blotting). The ideal bio- due to floor and ceiling effects. The MFM motor func- marker would be one that can be reliably measured in a tion scale has been developed to assess motor function blood sample of reasonably small volume, that is sensi- in several neuromuscular diseases including SMA tive to change, and that reflects biological activity in the [33,34]. Spinal fusion can influence motor function spinal cord. scores as it interferes with some tasks, e. g. rolling. 504 P. 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Possible respiratory measures include spirometry treatments. Trials should target a broad spectrum of (FVC, FEV1), peak inspiratory pressures, and peak the SMA population and minimize patient exclusion, cough flow. Nocturnal oxygen saturation and end-tidal as long as this does not threaten the scientific integrity carbon dioxide tensions can be studied. of the trial. In a relatively rare disease with a limited Possible motor strength measures include manual number of possible trial participants, clinical trials that muscle testing, myometry using a handheld dynamome- can collect data of sufficient quality while being per- ter, or quantitative muscle testing using a fixed system formed outside of major academic medical centers [30]. would allow patients from a larger geographic area to The secondary outcomes may include additional func- participate. tional measures not considered as primary outcome as Study groups should aim for consensus on a mini- well as MUNE, DXA or biological outcome measures mum core set of common design features and outcome (see above). measures so that data can be compared between trials. Quality of life and caregiver burden measures should This would likely facilitate the expansion to additional be included among the secondary outcomes. General sites as needed in future Phase III trials. Data from com- QoL measures have been used in SMA, e.g., PedsQoL pleted trials could be submitted to a data warehouse and [30]. Disease-specific QoL measures are under develop- be made available to investigators for meta-analyses and ment [35]. for the planning of clinical trials. All Phase III trials should be randomized, double- 11.3. Duration of follow-up period and frequency of visits blind, and placebo-controlled, and all should require the primary statistical analysis to be performed accord- Generally, an SMA trial should be as short as possi- ing to the intention to treat principle. ble. For SMA Type 2 or 3 trials it seems less likely that a Given that there are a number of potential treatments meaningful change in motor function could be observed for SMA based on in vitro studies, and given the relative over a 3 month period than for example over a 9–12 rarity of the disease and thus the limited patient pool, month period. Also, a somewhat longer duration of fol- efficiency and investigator collaboration are key in low-up than for SMA Type 1 trials may be acceptable SMA clinical trials. given the more benign phenotype. However, any study duration of greater than 12 months may likely be less acceptable to families. List of participants The duration for a study of Type 2 SMA will depend on the outcome measure, the anticipated mechanism of P. Kaufmann (New York, USA) action of the study medication, and the magnitude and F. Muntoni (London, UK) time course of the expected effect. The visit schedule E. Bertini (Rome, Italy) has to be acceptable to families and the evaluations at R. Finkel (Philadelphia, PA, USA) a given visit have to be planned with consideration to L. Hynan (Dallas, TX, USA) patient and family burden. J. Kissel (Columbus, OH, USA) B. LaSalle (Salt Lake City, UT, USA) z 12. Summary/Conclusion A. Macaulay (Stratford-upon-Avon, UK) M. McDermott (Rochester, NY, USA) Several compounds are currently available for SMA A. Meguiar (Richmond Hill, GA, USA) clinical testing and more are expected to move along J. Melki (Evry, France) the ‘‘pipeline’’ of SMA drug development. To evaluate U. Mellies (Essen, Germany) these new treatments in a timely fashion, the following T. Nguyen (Rockville, MD, USA) issues should be considered when designing clinical K. Swoboda (Salt Lake City, UT, USA) trials: C. Wang (Stanford, CA, USA) Researchers and patient advocates should collaborate B. Wong (Cincinnati, OH, USA) starting in the planning stages of a clinical trial to design studies that will be acceptable and supported by fami- Based on discussions during conference calls and lies. More education of physicians, patients and families meeting on June 24, 2005 in Philadelphia (9th Annual is needed regarding the benefits of participating in a ran- Spinal Muscular Atrophy Research Group Meeting). domized controlled clinical trial and the virtues of ran- domization, blinding, and appropriate controls. These steps will enhance recruitment and support for research in the SMA community. As many SMA patients as possible should have access to clinical trials to expedite evaluation of new z Deceased. P. Kaufmann, F. Muntoni / Neuromuscular Disorders 17 (2007) 499–505 505
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