FREEDOMS II- study (41), not included in Khai et al.(27) RCT identification NCT00355134
Appendix 5: GRADE evaluation of comparisons
Interferon beta-1a 22 mcg compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
1
Withdrawal due to adverse events
1
MD – mean difference, RR – relative risk
1. Only one study, not possible to check for inconsistency 2. Patients were treatment naïve.
3. For continuous outcomes, a sample size of approximately 400 may not be sufficient to insure prognostic balance (ref GRADE 6 paper).
4. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
5. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
172
Interferon beta-1a 30 mcg compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
3
Withdrawal due to adverse events
3
MD – mean difference, RR – relative risk
1. In the minor contributing study patients were treatment naïve.
2. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
3. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
173
Interferon beta-1a 44 mcg compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
2
124 fewer per 1000 (from 16 more
to 214 fewer) ⨁⨁◯◯
LOW 2 3 4 5
Withdrawal due to adverse events
1
MD – mean difference, RR – relative risk
1. In the major contributing study patients were treatment naïve.
2. Only one study, not possible to check for inconsistency 3. Patients were treatment naïve.
4. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
5. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
6. The effect estimate and the confidence interval are not robust. Minor variations in number of events would change the results.
174
Glatiramer acetate 20 mg compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
3
Withdrawal due to adverse events
3
MD – mean difference, RR – relative risk
1. In the minor contributing studies, patients were treatment naïve or had an unclear treatment history.
2. In the minor contributing study patients were treatment naïve.
3. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
4. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
175
Glatiramer acetate 40 mg compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
1
Withdrawal due to adverse events
1
MD – mean difference, RR – relative risk
1. Only one study, not possible to check for inconsistency
2. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
3. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
176
Dimethyl fumarate 240 mg two times daily compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate 2
78 fewer per 1000 (from 33 fewer to
114 fewer) ⨁⨁⨁⨁
HIGH
Withdrawal due to adverse events 2
MD – mean difference, RR – relative risk
1. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
2. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
177
Dimethyl fumarate 240 mg three times daily compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
2
71 fewer per 1000 (from 25 fewer to
107 fewer) ⨁⨁⨁⨁
HIGH
Withdrawal due to adverse events
2
MD – mean difference, RR – relative risk
1. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
2. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
178
Teriflunomide oral 7 mg compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
3
Withdrawal due to adverse events
3
MD – mean difference, RR – relative risk
1. In the minor contributing study patients were treatment naïve.
2. Only one study, not possible to check for inconsistency
3. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
4. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
179
Teriflunomide oral 14mg compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
3
Withdrawal due to adverse events
3
MD – mean difference, RR – relative risk
1. In the minor contributing study patients were treatment naïve.
2. Only one study, not possible to check for inconsistency
3. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
4. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
5. The effect estimate and the confidence interval are not robust. Minor variations in number of events would change the results.
180
Fingolimod oral 0.5 mg compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
3
Withdrawal due to adverse events
3
MD – mean difference, RR – relative risk
1. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
2. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
181
Fingolimod oral 1.25 mg compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
3
64 fewer per 1000 (from 17 fewer to
102 fewer) ⨁⨁⨁⨁
HIGH
Withdrawal due to adverse events
3
MD – mean difference, RR – relative risk
1. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
182
Peg-interferon beta-1a 125 mcg once every two weeks compared to Pla-cebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
1
Withdrawal due to adverse events
1
MD – mean difference, RR – relative risk
1. Only one study, not possible to check for inconsistency
2. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
3. The effect estimate and the confidence interval are not robust. Minor variations in number of events would change the results.
4. The effect estimate and the confidence interval are not robust. Minor variations in number of events would change the results.
183
Peg-interferon beta-1a 125 mcg once every four weeks compared to Pla-cebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
1
Withdrawal due to adverse events
1
MD – mean difference, RR – relative risk
1. Only one study, not possible to check for inconsistency
2. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
3. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
4. The effect estimate and the confidence interval are not robust. Minor variations in number of events would change the results
184
Natalizumab 300 mg intravenous every four weeks compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
2
118 fewer per 1000 (from 46 fewer
to 168 fewer) ⨁⨁⨁◯
MODER-ATE 3 4 5
Withdrawal due to adverse events
2
MD – mean difference, RR – relative risk
1. Heterogeneity may be explained by differences in study setting. One study compared natalizumab with placebo over a two years period while the other tested treatment interruption in natalizumab users
2. One study compared natalizumab with placebo over a two years period while the other tested treatment interruption in natalizumab users 3. Only one study, not possible to check for inconsistency
4. Patients’ treatment history was unclear.
5. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
6. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
185
Interferon beta-1b 250 mcg SC every other day compared to Placebo for RRMS
Quality assessment № of patients Effect
Quality
Annualised relapse rate
1
106 fewer per 1000 (from 78 more
to 230 fewer) ⨁⨁◯◯
LOW 1 2 4 5
Withdrawal due to adverse events
1
76 fewer per 1000 (from 43 fewer to
82 fewer) ⨁⨁◯◯
LOW 1 2 4 6
MD – mean difference, RR – relative risk
1. Only one study, not possible to check for inconsistency 2. Patients were treatment naïve.
3. For continuous outcomes, a sample size of approximately 400 may not be sufficient to insure prognostic balance (ref GRADE 6 paper).
4. Optimal information size (OIS) not met. For example, at least 200 events are required to meet OIS, based on a 25% relative risk reduction and control group risks of approximately 50% or greater (ref GRADE 6 paper).
5. The confidence interval (CI) includes both no effect, and the 25% threshold for appreciable benefit or harm. This corresponds to a CI that includes both 1.00, and 0.75 or 1.25 (ref GRADE 6 paper).
6. The effect estimate and the confidence interval are not robust. Minor variations in number of events would change the results.
186
Alemtuzumab 24 mg IV q.d compared to Alemtuzumab 12 mg IV q.d for