Transfer Factor Is Ineffective in Amyotrophic Lateral Sclerosis Marcelo R. Olarte, MD, Joanne C. G e r s t e n , MD, John Zabriskie, MD, a n d Lewis P. Rowland, MD
Sixty-six patients w i t h amyotrophic lateral sclerosis (ALS) participated in a double-blind, placebo-controlled study o f transfer factor. A structured r a t i n g score of neurological function was recorded a f t e r each monthly administration of transfer factor or placebo. Statistical analysis of mean scores for all patients and for those w i t h specific clinical abnormalities showed no significant difference between the two groups. There was n o evidence of therapeutic value for transfer factor. D u r i n g the observation period of nearly o n e year, more than two-thirds of the deterioration occurred in t h e first six months. Meaningful clinical trials of o t h e r potential therapeutic agents could probably b e conducted within six months in double-blind crossover trials. Olarte MR, Gersten JC, Zabriskie J, et al: Transfer factor is ineffective in amyotrophic lateral sclerosis. Ann Neurol 5:385-388, 1979
T h e r e is n o specific therapy for a m y o t r o p h i c lateral sclerosis (ALS), a n d this problem is c o m p o u n d e d by inappropriately optimistic r e p o r t s o f improperly controlled treatments. In contrast, adequately controlled studies showed lack of effect of snake v e n o m [123, guanidine [6, 71, isoprinosine 13, 101, and amantadine [ 2 ] . We n o w describe a n evaluation of transfer factor.
were followed from two to twenty-six months. There were no adverse reactions to the injections.
Preparation of Transfer Factor Leukocytes were isolated and transfer factor prepared as described elsewhere [ 11. The placebo was pyrogen-free distilled water from the same batch used to prepare the transfer factor. Solutions were stored at -70°C in tubes that appeared identical.
Methods
Statirtiral Analy.ri.r
Patients were accepted for the trial if the diagnosis was confirmed by two neurologists and if electrodiagnostic studies showed appropriate abnormalities. We included only patients with unequivocal signs of lower motor neuron disorder; therc were no patients with corticospinal signs alone, or with sensory loss. None had parathyroid disease, lead poisoning, or plasma cell dyscrasia. Otherwise eligible patients were excluded if they were relucant to participate in a double-blind study, if geography prevented monthly visits, or if they were receiving other treatment. The study patients (23 women and 43 men, aged 30 to 78 years) gave informed consent and were evaluated by the scoring system of Norris et a1 [ 7 ]and objectivc evaluation. A score of 100 reprcscnted normal neurological function. Each month patients were given injections of transfer factor or placebo and examined by M. Olarte, without reference to prior scores ro preclude observer bias. The study was double-blind. Random assignment of patients to control or treatment groups was performed by J. Gersten, who never saw the patients. J. Zabriskie prepared the transfer factor and solutions for placebo injections. The patients
The staggered entrance of patients into the trial meant that at a given date. not all participants had been observed for the same period. In addition, other problems prevented strict adherence to the constant interval of one month between injections and examinations. Therefore, within a certain interval (i.e., six months) the number of doses of drug or placebo was not identical in all patients. Because the number of doses might affect outcome, comparison between groups was done when the number of doses was held constant for the two groups. In other words, at each number of doses, a t test for independent groups was done to determine if treatment had a significant effect. (The number of doses did closely match time under observation, however.) In addition, regression coefficients were calculated for each group over the range of dosages to determine if there was a significant difference in rate of deterioration. When the trial was concluded after two years, 39 patients (59yt)had been randomly assigned to treatment and 41VF to placebo o r control. Analysis throughout the trial indicated that the large variance in individual functioning within the two groups impeded demonstration of sig-
From the H . Houston Merritt Clinical Research Center for Mus-
Accepted for publication Sept 19, 1978. Dr olarte, Neurological Institute, 7 10 Address reprint requests W 168th St, New York, NY 10032.
dar Dystrophy and Related Diseases,Columbia University COllege of Physicians and Surgeons, che School of Public Health, and the Neuroloaical Institute of the Presbyterian Hospital. and from the Rockefeller University, New York; N Y .
0364-5134/79/040385-04$01.25 @ 1978 by Marcelo R. Olarte
385
Table I. Characteristics of the Experimental and Control Patients Used for the Final Analysis
Characteristics of Subjects
Experimental Patients
Control Patients
Mean age (yr) Men ( c ? ) Women ( C i ) Range of doses Mean no. of doses
53.2 56.3 43.7 5-23
57.5 75.0 25.0 3-23 12.3
11.4
nificant differences. The large variance among scores within each group arose because patients entered the trial at diverse stages of the disease. Entering scores of neurological function ranged from 25 to 90 among the controls and from 32 to 90 in the experimental group. Because of this high variability, treatment would have to have a powerful effect for a significant difference to occur. For example, the standard deviation of scores of the fifth dosage point for the experimental group, when 11 patients were enrolled in the condition, was 23.4. Finding a significant difference between the two groups would require a mean difference of 19 or more points. Since entering scores in each group showed a range of about 60 points o n the 100point scale, a 307; differential in functioning between groups would be required to disprove the null hypothesis. The first task of the analysis, therefore, was to increase the statistical power of the trial so that nonsignificance of results, if found, would be attributable more to t h e ineffectiveness of treatment than to the lack of statistical power. Three basic hypotheses common to most of medicine, including this disease, were invoked to achieve this goal. We thought that greater homogeneity among patients would be achieved by application of the following principles: (1) effectiveness of treatment is a linear function of the extent to which the disease has progressed; ( 2 ) treatment started soon after diagnosis or "entrance into medical care" is likely to be more effective than treatment started later; and (3) patients should receive more than one dose of the therapeutic agent. The last principle also gives some assurance that the results reflect the actual treatment and not simply the early psychological benefits of receiving any treatment or attention. These principles were made operational by restricting analysis to patients who met the following criteria: (1)entered into the study with a score of at least 50; ( 2 ) received first dose of drug or placebo within 60 days after entry; and (3) were observed at least twice. Since the three criteria reduced the number of patients, a factor that itself reduces statistical power, the importance of the second criterion listed above was tested after the trial had proceeded for one year. To do this, we compared patients who met all three criteria with those who first received treatment or placebo after 60 days but otherwise met criteria 1 and 3 . Subjects who met all three criteria did not significantly differ from their controls across eight dosage points. This pattern was identical to that of experimental and control subjects who received the first dose of transfer factor or placebo after the 60-day interval. Therefore, the time of first administration of the drug did not significantly influence the results, and
386 Annals of Neurology
Vol 5 N o 4
April 1979
this criterion was dropped to obtain larger group frequencies. Analysis at the end of the trial included patients who met the dual criteria of having an entrance score of at least 50 and receiving at least two doses of transfer factor o r placebo and who, in addition, were still alive (Table 1 ).
Results T h e two groups were similar in most respects except that the controls ultimately included more men. T h e mean scores were computed at each dosage point for which scores were available for more than 5 patients in each group. Comparisons between means were d o n e at each dosage point, using a t test for independent groups (Table 2). T h e strategy for achieving greater homogeneity of the groups resulted in a substantial decrease in the variance within each group. However, there was n o significant difference between the means of experimental and control groups at any of the twelve observation points for about one year of continued observation. Regression coefficients for the two groups were calculated across the dosage levels, and both groups evidenced a significant negative linear trend. I n other words, both groups significantly deteriorated in neurological functioning during the year of observation. T h e r e was n o significant difference between t h e regression coefficients (trends) of the two groups. O v e r t h e o n e year, there was progressive deterioration in mean performance from 20 to 30% of initial scores. Transient improvement was not seen within a group. Therefore, transfer factor had n o effect in halting progressive deterioration. More than two-thirds of the deterioration occurred within six months of the first treatment. Since these results were obtained by considering only 42% of the patients who entered the trial, attention was also directed to the other patients. Forty percent of the patients had either died during the course of the trial or had discontinued the trial (equal numbers in each category). There was n o significant difference either in t h e proportion of deaths in experimental and control groups (20.5 and 18.55?, respectively) or in the proportion of those who discontinued the trial (38.5 and 40.7%). Most deaths occurred in t h e first six months of the trial, after a mean of 4.6 doses for the experimental g r o u p and 4.0 doses for the controls. Those w h o died in the experimental and control groups had nearly identical mean scores in pretest evaluations (67.4 and 69.2). Discontinuation occurred earlier in the trial than death, after an average of o n e dose for the experimental g r o u p and two doses for controls. Only 1 patient discontinued the trial after four treatments. The other 1 8 F of the patients were not included in the final analysis either because they did not have the
Table 2 . Neurological Function Scores for the Experimental and Control Gr0up.r at Eleven Time Points Control Group
Experimental Group Time Point Pretest After dose 1 After dose 2 After dose 3
After dose 4 After dose 5 After dose 6 After dose 7 After dose 8 After dose 9 After dose 10 After dose 11 Values are mean
No. of Patients
Function Score
NO. of Parienrs
Function Score
16 16 16 15 15 14 14 10
80.1 f 8.4 74.0 f 11.7 71.8 f 10.5 70.2 f 12.7 68.0 f 14.0 65.7 f 14.9 61.8 f 14.0 59.7 f 18.1 61.8 f 16.3 58.3 f 15.0 57.3 f 16.1 56.9 2 19.9
12 12 12
78.5 9.6 76.8 f 11.1 77.8 f 9.6 74.3 ? 11.7 72.3 13.1 70.0 15.3 67.2 f 16.0 66.9 19.6 68.8 ? 14.8 65.1 f 16.7 68.8 t 17.0 61.9 19.9
9 7 7 7 ?
*
11
* *
11 10 10
*
9 9 7 6 7
*
t Test
0.44 0.62 1.51 0.82 0.77 0.66 0.82 0.78 0.90 0.74 1.14 0.43
SD.
required entrance score ( 3 patients) or because they entered too late to have two treatments ( 9 patients). Discussion Transfer factor was used as a therapeutic agent because of the unproved suspicion that ALS may be due to persistent viral infection [8-111. Transfer factor is a substance of uncertain nature in human white cells [ 5 ] . When transfer factor from immune persons is injected into nonimmune subjects, lasting immunity is said to be transferred [ 5 ] , and the agent has been used to treat several diseases of known or unknown cause, including multiple sclerosis [ 11. No specific viral agent is recognized in ALS, but treatment was considered possible nevertheless. In similar circumstances, Lawrence [4] presumed that the infection in question would also have infected others exposed to the immediate environment of the patient. Because unaffected close relatives did not succumb to the disease, it was presumed that they were immune. In diseases of uncertain cause, therefore, transfer factor was prepared from close relatives of patients, and we adopted this technique to study transfer factor in ALS. However, the results indicated that transfer factor is not an effective treatment for ALS; it did not halt or slow the progressive deterioration, nor did it change the expectation of death. Based on our data, however, some practical suggestions may affect future trials of potential therapeutic agents. The greatest decline in functioning during observation for o n e year occurred in the first six months after the start of treatment. All discontinuations from the trial, as well as almost all deaths in both the experimental and control groups, occurred within the initial six months. Future clinical
trials should not require a treatment period as long as one year. A six-month treatment trial should be sufficient to include all major eve-its that might affect the trial. Given an adequately large patient sample that meets the dual criteria employed in this trial (N = 50),+a randomized crossover design with double-blind procedures in which patients are on drug or placebo for six months seems an appropriate alternative procedure and would be especially useful for therapeutic agents with adverse side-effects. This design would still entail a one-year study, but the patients would not be overexposed to the agent, and effectiveness of the agent could be gauged adequately. Finally, continuation of the trial for one year even though the potential agent is only involved for half that time seems to have important psychological benefits for the patients and for their physicians. "This estimate is based on a standard deviation of 14.9 in functional scores, the highest observed for the experimental group during the six-month period, a mean difference of 6.0, and a twotailed statistical hypothesis.
Supported by a grant from the Muscular Dystrophy Association.
References 1. Collins RC, Espinoza LR, Plank CR, et al: A double-blind trial of transfer factor vs. placebo in multiple sclerosis patients. Clin Exp Immunol (in press) 2. Engel WK. Hogenhuis LA, Collis WJ, et al: Metabolic studies and therapeutic trials in amyotrophic lateral sclerosis, in Morr i s FH, Kurland LT (eds): Motor Neuron Diseases. N e w York, Grune & Stratton, 1969, pp 199-213 3. Fareed G , Tyler HR: The use of isoprinosine in ALS. Neurology (Minneap) 21:937-940, 1971
Olarte et al: Transfer Factor in ALS
387
4. Lawrence HS: Transfer factor. Adv Immunol 11:195-266, 1969 5. Lawrence HS, Al-Askari S: The preparation and purification of transfer factor, in Bloom BR, Glade PR (eds): In Vitro Methods in Cell-Mediated Immunity. New York, Academic, 1971, pp 531-546 6. Norris EJ Jr: Guanidine in amyotrophic lateral sclerosis. N Engl J Med 288:690-691, 1973 7. Norris EJ Jr, Clanchini PR, Fallat RJ, e t al: T h e administration of guanidine in amyotrophic lateral sclerosis. Neurology (Minneap) 24:721-729, 1974 8. Oshiro LS, Cremer NE, Norris F H , et al: Viruslike particle in muscle from a patient with amyotrophic lateral sclerosis. Neur~ilogy(Minneap) 26:57-60. 1976
388 Annals of Neurology Vol 5 N o 4 April 1979
9. Pena CE: Viruslike particles in amyotrophic lateral sclerosis: electron microscopical study of a case. Ann Neurol 1:290297, 1977 10. Percy AK, David LE, Johnston DM, e t al: Failure of isoprinosine in amyotrophic lateral sclerosis. N E n d J Med 285:689. 1971 11. Pertschuk LP, Cook AW, Gupta JK, e t al: Jejunal immunopathy in amyotrophic lateral sclerosis and multiple sclerosis. Identification of viral antigens by irnrnunofluorescence. Lancer 1:1119-1125, 1977 12. Tyler HR: Treatment of amyotrophic lateral sclerosis in double-blind trial with modified neurotoxin. Neurology (in press)
Sixty-six patients w i t h amyotrophic lateral sclerosis (ALS) participated in a double-blind, placebo-controlled study o f transfer factor. A structured r a t i n g score of neurological function was recorded a f t e r each monthly administration of transfer factor or placebo. Statistical analysis of mean scores for all patients and for those w i t h specific clinical abnormalities showed no significant difference between the two groups. There was n o evidence of therapeutic value for transfer factor. D u r i n g the observation period of nearly o n e year, more than two-thirds of the deterioration occurred in t h e first six months. Meaningful clinical trials of o t h e r potential therapeutic agents could probably b e conducted within six months in double-blind crossover trials. Olarte MR, Gersten JC, Zabriskie J, et al: Transfer factor is ineffective in amyotrophic lateral sclerosis. Ann Neurol 5:385-388, 1979
T h e r e is n o specific therapy for a m y o t r o p h i c lateral sclerosis (ALS), a n d this problem is c o m p o u n d e d by inappropriately optimistic r e p o r t s o f improperly controlled treatments. In contrast, adequately controlled studies showed lack of effect of snake v e n o m [123, guanidine [6, 71, isoprinosine 13, 101, and amantadine [ 2 ] . We n o w describe a n evaluation of transfer factor.
were followed from two to twenty-six months. There were no adverse reactions to the injections.
Preparation of Transfer Factor Leukocytes were isolated and transfer factor prepared as described elsewhere [ 11. The placebo was pyrogen-free distilled water from the same batch used to prepare the transfer factor. Solutions were stored at -70°C in tubes that appeared identical.
Methods
Statirtiral Analy.ri.r
Patients were accepted for the trial if the diagnosis was confirmed by two neurologists and if electrodiagnostic studies showed appropriate abnormalities. We included only patients with unequivocal signs of lower motor neuron disorder; therc were no patients with corticospinal signs alone, or with sensory loss. None had parathyroid disease, lead poisoning, or plasma cell dyscrasia. Otherwise eligible patients were excluded if they were relucant to participate in a double-blind study, if geography prevented monthly visits, or if they were receiving other treatment. The study patients (23 women and 43 men, aged 30 to 78 years) gave informed consent and were evaluated by the scoring system of Norris et a1 [ 7 ]and objectivc evaluation. A score of 100 reprcscnted normal neurological function. Each month patients were given injections of transfer factor or placebo and examined by M. Olarte, without reference to prior scores ro preclude observer bias. The study was double-blind. Random assignment of patients to control or treatment groups was performed by J. Gersten, who never saw the patients. J. Zabriskie prepared the transfer factor and solutions for placebo injections. The patients
The staggered entrance of patients into the trial meant that at a given date. not all participants had been observed for the same period. In addition, other problems prevented strict adherence to the constant interval of one month between injections and examinations. Therefore, within a certain interval (i.e., six months) the number of doses of drug or placebo was not identical in all patients. Because the number of doses might affect outcome, comparison between groups was done when the number of doses was held constant for the two groups. In other words, at each number of doses, a t test for independent groups was done to determine if treatment had a significant effect. (The number of doses did closely match time under observation, however.) In addition, regression coefficients were calculated for each group over the range of dosages to determine if there was a significant difference in rate of deterioration. When the trial was concluded after two years, 39 patients (59yt)had been randomly assigned to treatment and 41VF to placebo o r control. Analysis throughout the trial indicated that the large variance in individual functioning within the two groups impeded demonstration of sig-
From the H . Houston Merritt Clinical Research Center for Mus-
Accepted for publication Sept 19, 1978. Dr olarte, Neurological Institute, 7 10 Address reprint requests W 168th St, New York, NY 10032.
dar Dystrophy and Related Diseases,Columbia University COllege of Physicians and Surgeons, che School of Public Health, and the Neuroloaical Institute of the Presbyterian Hospital. and from the Rockefeller University, New York; N Y .
0364-5134/79/040385-04$01.25 @ 1978 by Marcelo R. Olarte
385
Table I. Characteristics of the Experimental and Control Patients Used for the Final Analysis
Characteristics of Subjects
Experimental Patients
Control Patients
Mean age (yr) Men ( c ? ) Women ( C i ) Range of doses Mean no. of doses
53.2 56.3 43.7 5-23
57.5 75.0 25.0 3-23 12.3
11.4
nificant differences. The large variance among scores within each group arose because patients entered the trial at diverse stages of the disease. Entering scores of neurological function ranged from 25 to 90 among the controls and from 32 to 90 in the experimental group. Because of this high variability, treatment would have to have a powerful effect for a significant difference to occur. For example, the standard deviation of scores of the fifth dosage point for the experimental group, when 11 patients were enrolled in the condition, was 23.4. Finding a significant difference between the two groups would require a mean difference of 19 or more points. Since entering scores in each group showed a range of about 60 points o n the 100point scale, a 307; differential in functioning between groups would be required to disprove the null hypothesis. The first task of the analysis, therefore, was to increase the statistical power of the trial so that nonsignificance of results, if found, would be attributable more to t h e ineffectiveness of treatment than to the lack of statistical power. Three basic hypotheses common to most of medicine, including this disease, were invoked to achieve this goal. We thought that greater homogeneity among patients would be achieved by application of the following principles: (1) effectiveness of treatment is a linear function of the extent to which the disease has progressed; ( 2 ) treatment started soon after diagnosis or "entrance into medical care" is likely to be more effective than treatment started later; and (3) patients should receive more than one dose of the therapeutic agent. The last principle also gives some assurance that the results reflect the actual treatment and not simply the early psychological benefits of receiving any treatment or attention. These principles were made operational by restricting analysis to patients who met the following criteria: (1)entered into the study with a score of at least 50; ( 2 ) received first dose of drug or placebo within 60 days after entry; and (3) were observed at least twice. Since the three criteria reduced the number of patients, a factor that itself reduces statistical power, the importance of the second criterion listed above was tested after the trial had proceeded for one year. To do this, we compared patients who met all three criteria with those who first received treatment or placebo after 60 days but otherwise met criteria 1 and 3 . Subjects who met all three criteria did not significantly differ from their controls across eight dosage points. This pattern was identical to that of experimental and control subjects who received the first dose of transfer factor or placebo after the 60-day interval. Therefore, the time of first administration of the drug did not significantly influence the results, and
386 Annals of Neurology
Vol 5 N o 4
April 1979
this criterion was dropped to obtain larger group frequencies. Analysis at the end of the trial included patients who met the dual criteria of having an entrance score of at least 50 and receiving at least two doses of transfer factor o r placebo and who, in addition, were still alive (Table 1 ).
Results T h e two groups were similar in most respects except that the controls ultimately included more men. T h e mean scores were computed at each dosage point for which scores were available for more than 5 patients in each group. Comparisons between means were d o n e at each dosage point, using a t test for independent groups (Table 2). T h e strategy for achieving greater homogeneity of the groups resulted in a substantial decrease in the variance within each group. However, there was n o significant difference between the means of experimental and control groups at any of the twelve observation points for about one year of continued observation. Regression coefficients for the two groups were calculated across the dosage levels, and both groups evidenced a significant negative linear trend. I n other words, both groups significantly deteriorated in neurological functioning during the year of observation. T h e r e was n o significant difference between t h e regression coefficients (trends) of the two groups. O v e r t h e o n e year, there was progressive deterioration in mean performance from 20 to 30% of initial scores. Transient improvement was not seen within a group. Therefore, transfer factor had n o effect in halting progressive deterioration. More than two-thirds of the deterioration occurred within six months of the first treatment. Since these results were obtained by considering only 42% of the patients who entered the trial, attention was also directed to the other patients. Forty percent of the patients had either died during the course of the trial or had discontinued the trial (equal numbers in each category). There was n o significant difference either in t h e proportion of deaths in experimental and control groups (20.5 and 18.55?, respectively) or in the proportion of those who discontinued the trial (38.5 and 40.7%). Most deaths occurred in t h e first six months of the trial, after a mean of 4.6 doses for the experimental g r o u p and 4.0 doses for the controls. Those w h o died in the experimental and control groups had nearly identical mean scores in pretest evaluations (67.4 and 69.2). Discontinuation occurred earlier in the trial than death, after an average of o n e dose for the experimental g r o u p and two doses for controls. Only 1 patient discontinued the trial after four treatments. The other 1 8 F of the patients were not included in the final analysis either because they did not have the
Table 2 . Neurological Function Scores for the Experimental and Control Gr0up.r at Eleven Time Points Control Group
Experimental Group Time Point Pretest After dose 1 After dose 2 After dose 3
After dose 4 After dose 5 After dose 6 After dose 7 After dose 8 After dose 9 After dose 10 After dose 11 Values are mean
No. of Patients
Function Score
NO. of Parienrs
Function Score
16 16 16 15 15 14 14 10
80.1 f 8.4 74.0 f 11.7 71.8 f 10.5 70.2 f 12.7 68.0 f 14.0 65.7 f 14.9 61.8 f 14.0 59.7 f 18.1 61.8 f 16.3 58.3 f 15.0 57.3 f 16.1 56.9 2 19.9
12 12 12
78.5 9.6 76.8 f 11.1 77.8 f 9.6 74.3 ? 11.7 72.3 13.1 70.0 15.3 67.2 f 16.0 66.9 19.6 68.8 ? 14.8 65.1 f 16.7 68.8 t 17.0 61.9 19.9
9 7 7 7 ?
*
11
* *
11 10 10
*
9 9 7 6 7
*
t Test
0.44 0.62 1.51 0.82 0.77 0.66 0.82 0.78 0.90 0.74 1.14 0.43
SD.
required entrance score ( 3 patients) or because they entered too late to have two treatments ( 9 patients). Discussion Transfer factor was used as a therapeutic agent because of the unproved suspicion that ALS may be due to persistent viral infection [8-111. Transfer factor is a substance of uncertain nature in human white cells [ 5 ] . When transfer factor from immune persons is injected into nonimmune subjects, lasting immunity is said to be transferred [ 5 ] , and the agent has been used to treat several diseases of known or unknown cause, including multiple sclerosis [ 11. No specific viral agent is recognized in ALS, but treatment was considered possible nevertheless. In similar circumstances, Lawrence [4] presumed that the infection in question would also have infected others exposed to the immediate environment of the patient. Because unaffected close relatives did not succumb to the disease, it was presumed that they were immune. In diseases of uncertain cause, therefore, transfer factor was prepared from close relatives of patients, and we adopted this technique to study transfer factor in ALS. However, the results indicated that transfer factor is not an effective treatment for ALS; it did not halt or slow the progressive deterioration, nor did it change the expectation of death. Based on our data, however, some practical suggestions may affect future trials of potential therapeutic agents. The greatest decline in functioning during observation for o n e year occurred in the first six months after the start of treatment. All discontinuations from the trial, as well as almost all deaths in both the experimental and control groups, occurred within the initial six months. Future clinical
trials should not require a treatment period as long as one year. A six-month treatment trial should be sufficient to include all major eve-its that might affect the trial. Given an adequately large patient sample that meets the dual criteria employed in this trial (N = 50),+a randomized crossover design with double-blind procedures in which patients are on drug or placebo for six months seems an appropriate alternative procedure and would be especially useful for therapeutic agents with adverse side-effects. This design would still entail a one-year study, but the patients would not be overexposed to the agent, and effectiveness of the agent could be gauged adequately. Finally, continuation of the trial for one year even though the potential agent is only involved for half that time seems to have important psychological benefits for the patients and for their physicians. "This estimate is based on a standard deviation of 14.9 in functional scores, the highest observed for the experimental group during the six-month period, a mean difference of 6.0, and a twotailed statistical hypothesis.
Supported by a grant from the Muscular Dystrophy Association.
References 1. Collins RC, Espinoza LR, Plank CR, et al: A double-blind trial of transfer factor vs. placebo in multiple sclerosis patients. Clin Exp Immunol (in press) 2. Engel WK. Hogenhuis LA, Collis WJ, et al: Metabolic studies and therapeutic trials in amyotrophic lateral sclerosis, in Morr i s FH, Kurland LT (eds): Motor Neuron Diseases. N e w York, Grune & Stratton, 1969, pp 199-213 3. Fareed G , Tyler HR: The use of isoprinosine in ALS. Neurology (Minneap) 21:937-940, 1971
Olarte et al: Transfer Factor in ALS
387
4. Lawrence HS: Transfer factor. Adv Immunol 11:195-266, 1969 5. Lawrence HS, Al-Askari S: The preparation and purification of transfer factor, in Bloom BR, Glade PR (eds): In Vitro Methods in Cell-Mediated Immunity. New York, Academic, 1971, pp 531-546 6. Norris EJ Jr: Guanidine in amyotrophic lateral sclerosis. N Engl J Med 288:690-691, 1973 7. Norris EJ Jr, Clanchini PR, Fallat RJ, e t al: T h e administration of guanidine in amyotrophic lateral sclerosis. Neurology (Minneap) 24:721-729, 1974 8. Oshiro LS, Cremer NE, Norris F H , et al: Viruslike particle in muscle from a patient with amyotrophic lateral sclerosis. Neur~ilogy(Minneap) 26:57-60. 1976
388 Annals of Neurology Vol 5 N o 4 April 1979
9. Pena CE: Viruslike particles in amyotrophic lateral sclerosis: electron microscopical study of a case. Ann Neurol 1:290297, 1977 10. Percy AK, David LE, Johnston DM, e t al: Failure of isoprinosine in amyotrophic lateral sclerosis. N E n d J Med 285:689. 1971 11. Pertschuk LP, Cook AW, Gupta JK, e t al: Jejunal immunopathy in amyotrophic lateral sclerosis and multiple sclerosis. Identification of viral antigens by irnrnunofluorescence. Lancer 1:1119-1125, 1977 12. Tyler HR: Treatment of amyotrophic lateral sclerosis in double-blind trial with modified neurotoxin. Neurology (in press)
