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Trihexifenidilo para la distonía en la parálisis cerebral

Appendices

Appendix 1. Search strategies

1. Cochrane Register of Studies Online, which includes the Cochrane Developmental, Psychosocial and Learning Problems Specialised Register

Searched 25 May 2017 (6 records)

#1MESH DESCRIPTOR Cerebral Palsy
#2(cerebral pals*):TI,AB,KY
#3(Little* disease):TI,AB,KY
#4CP:TI,AB,KY
#5#1 OR #2 OR #3 OR #4
#6(Antimuscarinic* or Anti‐muscarinic*):TI,AB,KY
#7MESH DESCRIPTOR Antiparkinson Agents
#8((antiparkinsonian or anti‐parkinsonian)):TI,AB,KY
#9((Apotrihex or Apo‐Trihex)):TI,AB,KY
#10(Artane):TI,AB,KY
#11benzhexol*:TI,AB,KY
#12hipokinon*:TI,AB,KY
#13MESH DESCRIPTOR Muscarinic Antagonists
#14Parkinane:TI,AB,KY
#15Parkopan:TI,AB,KY
#16trihexan*:TI,AB,KY
#17MESH DESCRIPTOR Trihexyphenidyl
#18Trihexyphenidyl*:TI,AB,KY
#19((trihexidyl* or tri‐hexidyl*)):TI,AB,KY
#20#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19
#21#5 AND #20

2. MEDLINE Ovid

Searched 25 May 2017 (45 records)

1 Cerebral Palsy/
2 cerebral pals$.tw,kf.
3 Little$ disease.tw,kf.
4 CP.tw.
5 or/1‐4
6 (Antimuscarinic$ or Anti‐muscarinic$).mp.
7 Antiparkinson Agents/
8 (antiparkinsonian or anti‐parkinsonian).mp.
9 (Apotrihex or Apo‐Trihex).mp.
10 Artane.mp.
11 benzhexol$.mp.
12 hipokinon$.mp.
13 Muscarinic Antagonists/
14 Parkinane.mp.
15 Parkopan.mp.
16 trihexan$.mp.
17 Trihexyphenidyl/
18 Trihexyphenidyl$.mp.
19 (trihexidyl$ or tri‐hexidyl$).mp.
20 or/6‐19
21 5 and 20
22 randomized controlled trial.pt.
23 controlled clinical trial.pt.
24 randomi#ed.ab.
25 placebo$.ab.
26 drug therapy.fs.
27 randomly.ab.
28 trial.ab.
29 groups.ab.
30 or/22‐29
31 exp animals/ not humans.sh.
32 30 not 31
33 21 and 32

3. MEDLINE In‐Process & Other Non‐Indexed Citations Ovid

Searched 25 May 2017 (2 records)

1 cerebral pals$.af.
2 Little$ disease.af.
3 CP.af.
4 or/1‐3
5 (Antimuscarinic$ or Anti‐muscarinic$).af.
6 (antiparkinsonian or anti‐parkinsonian).af.
7 (Apotrihex or Apo‐Trihex).af.
8 Artane.af.
9 benzhexol$.af.
10 hipokinon$.af.
11 Parkinane.af.
12 Parkopan.af.
13 trihexan$.af
14 Trihexyphenidyl$.af.
15 (trihexidyl$ or tri‐hexidyl$).af.
16 or/5‐15
17 4 and 16

4. MEDLINE Epub Ahead of Print Ovid

Searched 25 May 2017 (0 records)

1 cerebral pals$.af.
2 Little$ disease.af.
3 CP.af.
4 or/1‐3
5 (Antimuscarinic$ or Anti‐muscarinic$).af.
6 (antiparkinsonian or anti‐parkinsonian).af.
7 (Apotrihex or Apo‐Trihex).af.
8 Artane.af.
9 benzhexol$.af.
10 hipokinon$.af.
11 Parkinane.af.
12 Parkopan.af.
13 trihexan$.af.
14 Trihexyphenidyl$.af.
15 (trihexidyl$ or tri‐hexidyl$).af.
16 or/5‐15
17 4 and 16

5. Embase Ovid

Searched 25 May 2017 (39 records)

1 cerebral palsy/
2 Littles disease.tw,kw.
3 cerebral pals$.tw,kw.
4 CP.tw,kw.
5 1 or 2 or 3 or 4
6 (Antimuscarinic$ or Anti‐muscarinic$).mp.
7 antiparkinson agent/
8 (antiparkinsonian or anti‐parkinsonian).mp.
9 (Apotrihex or Apo‐Trihex).mp.
10 Artane.mp.
11 benzhexol$.mp.
12 hipokinon$.mp.
13 muscarinic receptor blocking agent/
14 Parkinane.mp.
15 Parkopan.mp.
16 trihexan$.mp.
17 trihexyphenidyl/
18 Trihexyphenidyl$.mp.
19 (trihexidyl$ or tri‐hexidyl$).mp.
20 or/6‐19
21 5 and 20
22 Randomized controlled trial/
23 controlled clinical trial/
24 Single blind procedure/
25 Double blind procedure/
26 triple blind procedure/
27 Crossover procedure/
28 (crossover or cross‐over).tw.
29 ((singl$ or doubl$ or tripl$ or trebl$) adj1 (blind$ or mask$)).tw.
30 Placebo/
31 placebo.tw.
32 prospective.tw.
33 factorial$.tw.
34 random$.tw.
35 assign$.ab.
36 allocat$.tw.
37 volunteer$.ab.
38 or/22‐37
39 21 and 38

6. CINAHL Plus EBSCOhost (Cumulative Index to Nursing and Allied Health Literature)

Searched 25 May 2017 (12 records)

S20S5 AND S19
S19S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18
S18(trihexidyl* or tri‐hexidyl*)
S17Trihexyphenidyl*
S16trihexan*
S15Parkopan
S14Parkinane
S13(MH "Muscarinic Antagonists")
S12hipokinon*
S11benzhexol*
S10Artane
S9(Apotrihex or Apo‐Trihex)
S8(antiparkinsonian or anti‐parkinsonian)
S7(MH "Antiparkinson Agents")
S6(Antimuscarinic* or Anti‐muscarinic*)
S5S1 OR S2 OR S3 OR S4
S4TI (CP) or AB(CP)
S3Littles disease
S2cerebral pals*
S1(MH "Cerebral Palsy")

7. Science Citation Index Web of Science

Searched 26 May 2017 (37 records)

# 8 #7 AND #4
Indexes=SCI‐EXPANDED Timespan=1970‐2017
# 7 #6 OR #5
Indexes=SCI‐EXPANDED Timespan=1970‐2017
# 6 TS= (antiparkinsonian or "anti‐parkinsonian" or Antimuscarinic* or "Anti‐muscarinic*")
Indexes=SCI‐EXPANDED Timespan=1970‐2017
# 5 TS=(Apotrihex or "Apo‐Trihex" or Artane or benzhexol* or hipokinon* or Parkinane or Parkopan or trihexan* or Trihexyphenidyl* or trihexidyl* or tri‐hexidyl*)
Indexes=SCI‐EXPANDED Timespan=1970‐2017
# 4 #3 OR #2 OR #1
Indexes=SCI‐EXPANDED Timespan=1970‐2017
# 3 TS=(CP )
Indexes=SCI‐EXPANDED Timespan=1970‐2017
# 2 TS=(Little* disease)
Indexes=SCI‐EXPANDED Timespan=1970‐2017
# 1 TS=(cerebral pals*)
Indexes=SCI‐EXPANDED Timespan=1970‐2017

8. Conference Proceedings Citation Index – Science Web of Science

Searched 26 May 2017 (0 records)

# 8 #7 AND #4
Indexes=CPCI‐S Timespan=1990‐2017
# 7 #6 OR #5
Indexes=CPCI‐S Timespan=1990‐2017
# 6 TS= (antiparkinsonian or "anti‐parkinsonian" or Antimuscarinic* or "Anti‐muscarinic*")
Indexes=CPCI‐S Timespan=1990‐2017
# 5 TS=(Apotrihex or "Apo‐Trihex" or Artane or benzhexol* or hipokinon* or Parkinane or Parkopan or trihexan* or Trihexyphenidyl* or trihexidyl* or tri‐hexidyl*)
Indexes=CPCI‐S Timespan=1990‐2017
# 4 #3 OR #2 OR #1
Indexes=CPCI‐S Timespan=1990‐2017
# 3 TS=(CP)
Indexes=CPCI‐S Timespan=1990‐2017
# 2 TS=(Little* disease)
Indexes=CPCI‐S Timespan=1990‐2017
# 1 TS=(cerebral pals*)
Indexes=CPCI‐S Timespan=1990‐2017

9. Cochrane Database of Systematic Reviews (CDSR) part of the Cochrane Library

Searched 26 May 2017 (1 record)

#1[mh "Cerebral palsy"]
#2("cerebral pals*" or "Little* disease"):ti,ab
#3#1 or #2
#4[mh Trihexyphenidyl]
#5[mh "Muscarinic Antagonists"]
#6[mh ^"Antiparkinson Agents"]
#7Trihexyphenidyl*:ti,ab
#8benzhexol*:ti,ab
#9hipokinon*:ti,ab
#10trihexan*:ti,ab
#11Artane:ti,ab 10
#12(Parkopan or Parkinane):ti,ab
#13(Apotrihex or Apo next Trihex):ti,ab
#14(trihexidyl* or tri next hexidyl*):ti,ab
#15(Antimuscarinic* or Anti next muscarinic*):ti,ab
#16(antiparkinson* or anti next parkinson*):ti,ab
#17{or #4‐#16}
#18#3 and #17

10. Database of Abstracts of Reviews of Effects (DARE) part of the Cochrane Library

Searched 26 May 2017 (0 records)

#1[mh "Cerebral palsy"]
#2("cerebral pals*" or "Little* disease")
#3#1 or #2
#4[mh Trihexyphenidyl]
#5[mh "Muscarinic Antagonists"]
#6[mh ^"Antiparkinson Agents"]
#7Trihexyphenidyl*
#8benzhexol*
#9hipokinon*
#10trihexan*
#11Artane
#12(Parkopan or Parkinane)
#13(Apotrihex or Apo next Trihex)
#14(trihexidyl* or tri next hexidyl*)
#15(Antimuscarinic* or Anti next muscarinic*)
#16(antiparkinson* or anti next parkinson*)
#17{or #4‐#16}
#18#3 and #17

11. LILACS (lilacs.bvsalud.org/en)

Searched 26 May 2017 (3 records)

tw:((tw:(cerebral pals*)) AND (tw:(apotrihex OR "Apo‐Trihex" OR artane OR benzhexol* OR hipokinon* OR parkinane OR parkopan OR trihexan* OR trihexyphenidyl* OR trihexidyl* OR tri‐hexidyl* OR antiparkinsonian OR "anti‐parkinsonian" OR antimuscarinic* OR "Anti‐muscarinic*" ))) AND (instance:"regional") AND ( db:("LILACS"))

12. ClinicalTrials.gov

Searched 26 May 2017 (15 records*)

Basic search screen cerebral palsy AND dystonia (15 records)
or
Advanced search Condition| cerebral palsy AND Intervention| trihexyphenidyl (1 record)

*15 records after one duplicate removed

13. World Health Organisation International Clinical Trials Registry Platform (WHO ICTRP; who.int/ictrp/en)

Searched 26 May 2017 (17 records)

Basic search cerebral palsy AND dyston* (17)
ADVANCED SEARCH CONDITON| cerebral palsy AND INTERVENTION| Trihexyphenidyl (0)

Appendix 2. Criteria for assigning risks of bias

Sequence generation

  1. Low risk of bias: if a random component was used in the sequence generation process such as coin tossing, computer‐generated random numbers, or a table of random numbers

  2. High risk of bias: if a non‐random component was used in the sequence generation process

  3. Unclear risk of bias: if the sequence generation process was not described

Allocation concealment

  1. Low risk of bias: if participants and trial investigators had no foreknowledge (i.e. prior to eligibility decisions being made avn informed consent being obtained) of intervention assignment through the use of, for example, central allocation or sequentially numbered envelopes that were opaque and sealed

  2. High risk of bias: if participants and trial investigators had foreknowledge of intervention assignment

  3. Unclear risk of bias: if the method of allocation concealment was not described

Blinding of participants and personnel

  1. Low risk of bias: if there was no blinding or incomplete blinding but review authors judge the outcome is unlikely to have been influenced by the lack of blinding, or if blinding of study participants and personnel was ensured and it is unlikely that blinding could have been broken

  2. High risk of bias: if there was no blinding or incomplete blinding and the outcome was likely influenced by the lack of blinding, or if blinding of study participants and personnel was attempted but it is likely that blinding could have been broken and the outcome influenced by the lack of blinding

  3. Unclear risk of bias: if lack of information prohibits judgement of either low or high risk of bias, or if the study did not address this risk of bias

Blinding of outcome assessment

  1. Low risk of bias: if there was no blinding of outcome assessment but review authors judge that the outcome measurement is unlikely to have been influenced by lack of blinding, or if blinding of outcome assessment was ensured and it is unlikely that blinding could have been broken

  2. High risk of bias: if there was no blinding of outcome assessment and the outcome measurement was likely influenced by a lack of blinding, or if there was blinding of outcome assessment but it is likely that blinding could have been broken and the outcome measurement influenced by lack of blinding

  3. Unclear risk of bias: if lack of information prohibits judgement of either low or high risk of bias, or if the study did not address this risk of bias

Incomplete outcome data

  1. Low risk of bias: if no missing data were reported, or if appropriate methods were used to impute missing data, or if the reason for missing data is unlikely to be related to the true outcome

  2. High risk of bias: if missing data were reported and no appropriate methods were used to impute missing data, or if the reason for missing data is likely to be related to the true outcome

  3. Unclear risk of bias: if lack of information prohibits judgement of either low or high risk of bias, or if the study did not address this risk of bias

Selective reporting

  1. Low risk of bias: if a study has a protocol and all prespecified outcomes have been reported in the prespecified manner, or if a study has no protocol but all expected outcomes have been reported

  2. High risk of bias: if a study has a protocol and one or more prespecified outcomes have not been reported or have been reported in a manner that was not prespecified, or if a study has no protocol and all expected outcomes have not been reported

  3. Unclear risk of bias: if lack of information prohibits judgement of either low or high risk of bias

Other sources of bias

  1. Low risk of bias: if no other sources of bias (e.g. contamination or recruitment bias) appear to exist

  2. High risk of bias: if other sources of bias exist

  3. Unclear risk of bias: if lack of information permits judgement of whether other sources of bias exist

Study flow diagram.
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Figure 1

Study flow diagram.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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ANCOVA analyses, page 1
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Figure 3

ANCOVA analyses, page 1

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ANCOVA analyses, page 2
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Figure 4

ANCOVA analyses, page 2

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Comparison 1 Trihexphenidyl versus placebo, Outcome 1 Adverse effects.
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Analysis 1.1

Comparison 1 Trihexphenidyl versus placebo, Outcome 1 Adverse effects.

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Summary of findings for the main comparison. Summary of findings: Trihexyphenidyl compared with placebo for dystonia in cerebral palsy

Trihexyphenidyl compared with placebo for dystonia in cerebral palsy

Patient or population: children with dystonic cerebral palsy

Settings: one tertiary care hospital

Intervention: trihexyphenidyl

Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Placebo

Trihexyphenidyl

Change in dystonia from baseline

Measured by: BADS (eight body regions assessed for dystonia on a five‐point scale (0 = none to 4 = severe), minimum score 0 to maximum score 32; higher score = greater severity of dystonia)

Follow‐up: 12 weeks

The mean follow‐up score in the control group was 15.50 points

The mean follow‐up score in the intervention group was 2.67 points higher (2.55 lower to 7.90 higher)

—

16
1 (RCT)

⊕⊕⊝⊝

Lowa

Adverse effectsb (mood disturbance, irritability, behavioural change, constipation)

Measured by: counts of number and type

Follow‐up: various (includes data assessed at both 12 and 28 weeks)

375 per 1000

1000 per 1000

RR 2.54 (1.38 to 4.67)

16
1 (RCT)

⊕⊕⊝⊝
Lowa

Participation in activities of daily living:individual goal setting

Measured by: GAS (up to 5 functional goals scored on a 5‐point scale (−2 = much less than expected to +2 = much more than expected); higher score = better than expected outcome)

Follow‐up: 12 weeks

The mean follow‐up score in the control group was 27.63 points

The mean follow‐up score in the intervention group was 18.86 points higher (5.68 higher to 32.03 higher)

—

16
1 (RCT)

⊕⊕⊝⊝
Lowa

Participation in activities of daily living:satisfaction with individual goals

Measured by: satisfaction subscale of the COPM (satisfaction with performance in up to 5 problem areas scored on a 10‐point scale (1 = not satisfied at all to 10 = extremely satisfied); higher score = greater satisfaction)

Follow‐up: 12 weeks

The mean follow‐up score in the control group was 2.96 points

The mean follow‐up score in the intervention group was 2.91 points higher (1.01 higher to 4.82 higher)

—

16
1 (RCT)

⊕⊕⊝⊝
Lowa

Participation in activities of daily living:performance of individual goals

Measured by: performance subscale of the COPM (up to five problem areas scored on a 10‐point scale (1 = not able to do to 10 = able to do extremely well; higher score = better performance)

Follow‐up: 12 weeks

The mean follow‐up score in the control group was 3.14 points

The mean follow‐up score in the intervention group was2.24 points higher (0.64 higher to 3.84 higher)

—

16
1 (RCT)

⊕⊕⊝⊝
Lowa

Quality of life

Not measured

*The basis for the assumed risk is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
BADS: Barry Albright Dystonia Scale; CI: Confidence interval; COPM: Canadian Occupational Performance Measure; GAS: Goal Attainment Scale; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High quality: we are very confident that the true effect lies close to that of the estimate of effect
Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different
Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of effect
Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect

aDowngraded two levels due to imprecision; small sample size from one study only.
bAll side effects were counted as adverse effects, as defined in our protocol (Baker 2017). Adverse effect data was from both phases. It was not possible to obtain adverse effect data from the first phase only. All children were reported to have adverse effects in the treatment phase. Six out of 16 participants were reported to have adverse effects in the placebo phase; however, the timing of these is not clear. The estimated number of adverse effects in the placebo phase may therefore be lower and we may be underestimating the relative risk.

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Summary of findings for the main comparison. Summary of findings: Trihexyphenidyl compared with placebo for dystonia in cerebral palsy
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Table 1. Unused methods

Method

Unused methods

Measures of treatment effect

Continuous data

For continuous outcomes we will calculate the MD and corresponding 95% CI if studies use the same rating scales. We will calculate the SMD with 95% CIs if studies use different scales to measure the same outcomes.

As recommended in section 9.4.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017), we will focus on final values unless some of the studies use change scores. We will combine studies that report final values with studies that report only change scores in the same meta‐analysis, provided that the studies use the same rating scale.

We will conduct the analysis according to age, as children and adults respond differently to medication. We will combine the data from all groups in studies that have trihexyphenidyl in more than one group (i.e. different frequencies) and then separate these when performing the subgroup analysis to see how the different frequencies influence the results (see item four in the Subgroup analysis and investigation of heterogeneity section).

Multiple outcomes

If studies provide multiple, interchangeable measures of the same construct at the same point in time, we will calculate the average SMD across the outcomes and the average estimated variances, as recommended in section 16.1.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

Unit of analysis issues

Cluster‐RCTs

If included trials use cluster randomisation, we will extract an ICC and use this to reanalyse the data. Where no ICC is given and a unit of analysis error appears to exist, we will contact the trial authors and ask them to provide either an ICC or the raw data to enable calculation of an ICC. Where no ICC is made available, we will search for similar studies from which we can impute an ICC, or seek statistical advice to obtain an estimate of the ICC.

Dealing with missing data

We will contact trial investigators to request missing data. If the trialists provide missing data, we will conduct a meta‐analysis according to intention‐to‐treat principles using all data and keeping participants in the treatment group to which they were originally randomised, regardless of the treatment they actually received, as recommended in section 16.1.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). If missing data are not provided, we will analyse only the available data. If there is concern regarding a high level of missing data, such that data could not be included in a meta‐analysis, we will include a qualitative summary in the text of the review. We will document missing data and attrition in the 'Risk of bias' tables, and we will explore how missing data might affect the interpretation of the results by conducting a sensitivity analysis.

Assessment of heterogeneity

We will assess clinical heterogeneity by comparing the between‐trials distribution of participant characteristics (e.g. children versus adults) and intervention characteristics (e.g. treatment type and dose), and assess methodological heterogeneity by comparing trial characteristics (e.g. cross‐over versus parallel design). We will evaluate statistical heterogeneity using the I2 statistic and the Chi2 test of heterogeneity, with statistical significance set at P value < 0.10. As recommended in section 9.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017), we will consider I2 values as follows.

  1. 0% to 40% might not be important.

  2. 30% to 60% may represent moderate heterogeneity.

  3. 50% to 90% may represent substantial heterogeneity.

  4. 75% to 100% represents considerable heterogeneity.

We will report Tau2 as an estimate of the between‐study variance when reporting the results from the random‐effects model.

Assessment of reporting biases

If we identify 10 or more studies, we will use funnel plots to investigate the relationship between intervention effect and study size. We will explore possible reasons for any asymmetry found. We will analyse the funnel plot of the data to ascertain asymmetry. Asymmetry of a funnel plot may indicate, among other things, publication bias or poor methodological quality (Egger 1997).

Data synthesis

We will synthesise results in a meta‐analysis using a fixed‐effect model when studies are similar enough with regard to the intervention, population and methods, to assume that the same treatment effect is estimated. We will synthesise results in a meta‐analysis using a random‐effects model when statistical heterogeneity is found or when studies differ enough with regard to the intervention, population, and methods, to assume that different yet related treatment effects are estimated, and when it is deemed to be clinically relevant, as recommended in section 9.4.3.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017).

Subgroup analysis and investigation of heterogeneity

We will conduct the subgroup analyses listed below.

  1. Classification of cerebral palsy according to motor ability using the Gross Motor Function Classification System.Movement disorder and whether or not there is a mixed pattern (spasticity, dystonia, ataxic, choreoathetoid, hypotonic, mixed).

  2. Participant age (e.g. adults versus children, preschool children versus school‐age children).

  3. Treatment dosage and frequency of medication (2 versus 3 times a day; and low dose versus high dose).

  4. Polypharmacy: whether sole agents or other agents are used (trihexyphenidyl alone versus trihexyphenidyl and another agent).

  5. Length of follow‐up (e.g. ≤ 3 months versus > 3 months).

We will also look at the number of participants per study to determine if this is sufficient to perform a subgroup analysis.

Sensitivity analysis

We will conduct sensitivity analyses to investigate the effect on the overall results of excluding trials that meet the criteria described below.

  1. Inadequate allocation concealment or sequence generation (selection bias)

  2. No blinding (performance bias)

  3. Incomplete outcome data (attrition bias). To investigate the effect of incomplete outcome data we will re‐perform the meta‐analysis including only those studies with high rates of complete data and compare this result to the full meta‐analysis that contains studies with both high and low rates of complete outcome data (i.e. all included studies). In this way we will be able to determine if the results of the full meta‐analysis remain true and have not been influenced by incomplete outcome data.

We will also conduct a sensitivity analysis for studies with very low risk of bias. In addition, we will conduct a sensitivity analysis using a range of ICCs to assess the impact on treatment effect.

CI: confidence intervals; ICC: intraclass correlation coefficient; MD: mean difference; SMD: standardised mean difference.

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Table 1. Unused methods
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Comparison 1. Trihexphenidyl versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse effects Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected
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Comparison 1. Trihexphenidyl versus placebo
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